@article {472, title = {Genome-Wide Analyses of Vocabulary Size in Infancy and Toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits}, journal = {Biological Psychiatry}, volume = {95}, year = {2024}, month = {2024/05/01}, pages = {859 - 869}, abstract = {

BackgroundThe number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta?genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD).BackgroundThe number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta?genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD).

}, isbn = {0006-3223}, doi = {10.1016/j.biopsych.2023.11.025}, author = {Verhoef, Ellen and Allegrini, Andrea G. and Jansen, Philip R. and Lange, Katherine and Wang, Carol A. and Morgan, Angela T. and Ahluwalia, Tarunveer S. and Symeonides, Christos and Andreassen, Ole A. and Bartels, Meike and Boomsma, Dorret and Dale, Philip S. and Ehli, Erik and Fernandez-Orth, Dietmar and Guxens, M{\`o}nica and Hakulinen, Christian and Harris, Kathleen Mullan and Haworth, Simon and de Hoyos, Luc{\'\i}a and Jaddoe, Vincent and Keltikangas-J{\"a}rvinen, Liisa and Lehtim{\"a}ki, Terho and Middeldorp, Christel and Min, Josine L. and Mishra, Pashupati P. and Nj{\o}lstad, P{\r a}l Rasmus and Sunyer, Jordi and Tate, Ashley E. and Timpson, Nicholas and van der Laan, Camiel and Vrijheid, Martine and Vuoksimaa, Eero and Whipp, Alyce and Ystrom, Eivind and ACTION Consortium and Barwon Infant Study investigator group and Eising, Else and Franken, Marie-Christine and Hypponen, Elina and Mansell, Toby and Olislagers, Mitchell and Omerovic, Emina and Rimfeld, Kaili and Schlag, Fenja and Selzam, Saskia and Shapland, Chin Yang and Tiemeier, Henning and Whitehouse, Andrew J.O. and Saffery, Richard and B{\o}nnelykke, Klaus and Reilly, Sheena and Pennell, Craig E. and Wake, Melissa and Cecil, Charlotte A.M. and Plomin, Robert and Fisher, Simon E. and St. Pourcain, Beate} } @article {468, title = {Beyond the global brain differences: Intra-individual variability differences in 1q21.1 distal and 15q11.2 {BP1-BP2} deletion carriers}, journal = {Biological Psychiatry}, year = {2023}, abstract = {

BACKGROUND: The 1q21.1 distal and 15q11.2 BP1-BP2 CNVs exhibit regional and global brain differences compared to non-carriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intra-individual variability measures can be used to test for regional differences beyond global differences in brain structure.

METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n=30) and duplication (n=27), and 15q11.2 BP1-BP2 deletion (n=170) and duplication (n=243) carriers and matched non-carriers (n=2,350). Regional intra-deviation (RID) scores i.e., the standardized difference between an individual\&$\#$39;s regional difference and global difference, were used to test for regional differences that diverge from the global difference.

RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate and temporal pole differed less, and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex and temporal pole differed less, and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.

CONCLUSION: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 CNVs. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 CNVs, with the potential to increase our understanding of mechanisms involved in altered neurodevelopment.

}, keywords = {15q11.2 BP1-BP2, 1q21.1 distal, brain structure, copy number variants, intra-individual variability, magnetic resonance imaging}, doi = {10.1016/j.biopsych.2023.08.018}, author = {Boen, Rune and Kaufmann, Tobias and van der Meer, Dennis and Frei, Oleksandr and Agartz, Ingrid and Ames, David and Andersson, Micael and Armstrong, Nicola J and Artiges, Eric and Atkins, Joshua R and Bauer, Jochen and Benedetti, Francesco and Boomsma, Dorret I and Brodaty, Henry and Brosch, Katharina and Buckner, Randy L and Cairns, Murray J and Calhoun, Vince and Caspers, Svenja and Cichon, Sven and Corvin, Aiden P and Facorro, Benedicto Crespo and Dannlowski, Udo and David, Friederike S and de Geus, Eco J C and de Zubicaray, Greig I and Desrivieres, Sylvane and Doherty, Joanne L and Donohoe, Gary and Ehrlich, Stefan and Eising, Else and Espeseth, Thomas and Fisher, Simon E and Forstner, Andreas J and Uy{\`a}, Lidia Fortaner and Frouin, Vincent and Fukunaga, Masaki and Ge, Tian and Glahn, David C and Goltermann, Janik and Grabe, Hans J and Green, Melissa J and Groenewold, Nynke A and Grotegerd, Dominik and Hahn, Tim and Hashimoto, Ryota and Hehir-Kwa, Jayne Y and Henskens, Frans A and Holmes, Avram J and Haberg, Asta K and Haavik, Jan and Jacquemont, S{\'e}bastien and Jansen, Andreas and Jockwitz, Christiane and J{\"o}nsson, Erik G and Kikuchi, Masataka and Kircher, Tilo and Kumar, Kuldeep and Le Hellard, Stephanie and Leu, Costin and Linden, David E and Liu, Jingyu and Loughnan, Robert and Mather, Karen A and McMahon, Katie L and McRae, Allan F and Medland, Sarah E and Meinert, Susanne and Moreau, Clara A and Morris, Derek W and Mowry, Bryan J and M{\"u}hleisen, Thomas W and Nenadi{\'c}, Igor and N{\"o}then, Markus M and Nyberg, Lars and Owen, Michael J and Paolini, Marco and Paus, Tomas and Pausova, Zdenka and Persson, Karin and Quid{\'e}, Yann and Marques, Tiago Reis and Sachdev, Perminder S and Sando, Sigrid B and Schall, Ulrich and Scott, Rodney J and Selb{\ae}k, Geir and Shumskaya, Elena and Silva, Ana I and Sisodiya, Sanjay M and Stein, Frederike and Stein, Dan J and Straube, Benjamin and Streit, Fabian and Strike, Lachlan T and Teumer, Alexander and Teutenberg, Lea and Thalamuthu, Anbupalam and Tooney, Paul A and Tordesillas-Guti{\'e}rrez, Diana and Trollor, Julian N and Ent, Dennis van {\textquoteright}t and van den Bree, Marianne B M and van Haren, Neeltje E M and Vazquez-Bourgon, Javier and V{\"o}lzke, Henry and Wen, Wei and Wittfeld, Katharina and Ching, Christopher R K and Westlye, Lars T and Thompson, Paul M and Bearden, Carrie E and Selmer, Kaja K and Aln{\ae}s, Dag and Andreassen, Ole A and Sonderby, Ida E} } @article {448, title = {Discovery of 42 genome-wide significant loci associated with dyslexia}, journal = {Nature Genetics}, volume = {54}, year = {2022}, pages = {1621{\textendash}1629}, abstract = {

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70\%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6\% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

}, doi = {10.1038/s41588-022-01192-y}, author = {Doust, Catherine and Fontanillas, Pierre and Eising, Else and Gordon, Scott D and Wang, Zhengjun and Alag{\"o}z, G{\"o}kberk and Molz, Barbara and 23andMe Research Team and Quantitative Trait Working Group of the GenLang Consortium and Pourcain, Beate St and Francks, Clyde and Marioni, Riccardo E and Zhao, Jingjing and Paracchini, Silvia and Talcott, Joel B and Monaco, Anthony P and Stein, John F and Gruen, Jeffrey R and Olson, Richard K and Willcutt, Erik G and DeFries, John C and Pennington, Bruce F and Smith, Shelley D and Wright, Margaret J and Martin, Nicholas G and Auton, Adam and Bates, Timothy C and Fisher, Simon E and Luciano, Michelle} } @article {463, title = {DNA methylation in peripheral tissues and left-handedness}, journal = {Scientific Reports}, volume = {12}, year = {2022}, pages = {5606}, abstract = {

Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.

}, doi = {10.1038/s41598-022-08998-0}, author = {Odintsova, Veronika V and Suderman, Matthew and Hagenbeek, Fiona A and Caramaschi, Doretta and Hottenga, Jouke-Jan and Pool, Ren{\'e} and BIOS Consortium and Dolan, Conor V and Ligthart, Lannie and van Beijsterveldt, Catharina E M and Willemsen, Gonneke and de Geus, Eco J C and Beck, Jeffrey J and Ehli, Erik A and Cuellar-Partida, Gabriel and Evans, David M and Medland, Sarah E and Relton, Caroline L and Boomsma, Dorret I and van Dongen, Jenny} } @article {459, title = {Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people}, journal = {Proceedings of the National Academy of Sciences (PNAS)}, volume = {119}, year = {2022}, pages = {e2202764119}, abstract = {

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80\% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 \× 10\−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26\% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

}, keywords = {genome-wide association study, language, meta-analysis, reading}, doi = {10.1073/pnas.2202764119}, author = {Eising, Else and Mirza-Schreiber, Nazanin and de Zeeuw, Eveline L and Wang, Carol A and Truong, Dongnhu T and Allegrini, Andrea G and Shapland, Chin Yang and Zhu, Gu and Wigg, Karen G and Gerritse, Margot L and Molz, Barbara and Alag{\"o}z, G{\"o}kberk and Gialluisi, Alessandro and Abbondanza, Filippo and Rimfeld, Kaili and van Donkelaar, Marjolein and Liao, Zhijie and Jansen, Philip R and Andlauer, Till F M and Bates, Timothy C and Bernard, Manon and Blokland, Kirsten and Bonte, Milene and B{\o}rglum, Anders D and Bourgeron, Thomas and Brandeis, Daniel and Ceroni, Fabiola and Cs{\'e}pe, Val{\'e}ria and Dale, Philip S and de Jong, Peter F and DeFries, John C and D{\'e}monet, Jean-Fran\c cois and Demontis, Ditte and Feng, Yu and Gordon, Scott D and Guger, Sharon L and Hayiou-Thomas, Marianna E and Hern{\'a}ndez-Cabrera, Juan A and Hottenga, Jouke-Jan and Hulme, Charles and Kere, Juha and Kerr, Elizabeth N and Koomar, Tanner and Landerl, Karin and Leonard, Gabriel T and Lovett, Maureen W and Lyytinen, Heikki and Martin, Nicholas G and Martinelli, Angela and Maurer, Urs and Michaelson, Jacob J and Moll, Kristina and Monaco, Anthony P and Morgan, Angela T and N{\"o}then, Markus M and Pausova, Zdenka and Pennell, Craig E and Pennington, Bruce F and Price, Kaitlyn M and Rajagopal, Veera M and Ramus, Franck and Richer, Louis and Simpson, Nuala H and Smith, Shelley D and Snowling, Margaret J and Stein, John and Strug, Lisa J and Talcott, Joel B and Tiemeier, Henning and van der Schroeff, Marc P and Verhoef, Ellen and Watkins, Kate E and Wilkinson, Margaret and Wright, Margaret J and Barr, Cathy L and Boomsma, Dorret I and Carreiras, Manuel and Franken, Marie-Christine J and Gruen, Jeffrey R and Luciano, Michelle and M{\"u}ller-Myhsok, Bertram and Newbury, Dianne F and Olson, Richard K and Paracchini, Silvia and Paus, Tom{\'a}\v s and Plomin, Robert and Reilly, Sheena and Schulte-K{\"o}rne, Gerd and Tomblin, J Bruce and van Bergen, Elsje and Whitehouse, Andrew J O and Willcutt, Erik G and St Pourcain, Beate and Francks, Clyde and Fisher, Simon E} } @article {469, title = {Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention}, journal = {Nature Genetics}, volume = {54}, year = {2022}, pages = {1332{\textendash}1344}, abstract = {

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

}, doi = {10.1038/s41588-022-01165-1}, author = {Wang, Zhe and Emmerich, Andrew and Pillon, Nicolas J and Moore, Tim and Hemerich, Daiane and Cornelis, Marilyn C and Mazzaferro, Eugenia and Broos, Siacia and Ahluwalia, Tarunveer S and Bartz, Traci M and Bentley, Amy R and Bielak, Lawrence F and Chong, Mike and Chu, Audrey Y and Berry, Diane and Dorajoo, Rajkumar and Dueker, Nicole D and Kasbohm, Elisa and Feenstra, Bjarke and Feitosa, Mary F and Gieger, Christian and Graff, Mariaelisa and Hall, Leanne M and Haller, Toomas and Hartwig, Fernando P and Hillis, David A and Huikari, Ville and Heard-Costa, Nancy and Holzapfel, Christina and Jackson, Anne U and Johansson, \AAsa and J{\o}rgensen, Anja Moltke and Kaakinen, Marika A and Karlsson, Robert and Kerr, Kathleen F and Kim, Boram and Koolhaas, Chantal M and Kutalik, Zoltan and Lagou, Vasiliki and Lind, Penelope A and Lorentzon, Mattias and Lyytik{\"a}inen, Leo-Pekka and Mangino, Massimo and Metzendorf, Christoph and Monroe, Kristine R and Pacolet, Alexander and P{\'e}russe, Louis and Pool, Ren{\'e} and Richmond, Rebecca C and Rivera, Natalia V and Robiou-du-Pont, Sebastien and Schraut, Katharina E and Schulz, Christina-Alexandra and Stringham, Heather M and Tanaka, Toshiko and Teumer, Alexander and Turman, Constance and van der Most, Peter J and Vanmunster, Mathias and van Rooij, Frank J A and van Vliet-Ostaptchouk, Jana V and Zhang, Xiaoshuai and Zhao, Jing-Hua and Zhao, Wei and Balkhiyarova, Zhanna and Balslev-Harder, Marie N and Baumeister, Sebastian E and Beilby, John and Blangero, John and Boomsma, Dorret I and Brage, Soren and Braund, Peter S and Brody, Jennifer A and Bruinenberg, Marcel and Ekelund, Ulf and Liu, Ching-Ti and Cole, John W and Collins, Francis S and Cupples, L Adrienne and Esko, T{\~o}nu and Enroth, Stefan and Faul, Jessica D and Fernandez-Rhodes, Lindsay and Fohner, Alison E and Franco, Oscar H and Galesloot, Tessel E and Gordon, Scott D and Grarup, Niels and Hartman, Catharina A and Heiss, Gerardo and Hui, Jennie and Illig, Thomas and Jago, Russell and James, Alan and Joshi, Peter K and Jung, Taeyeong and K{\"a}h{\"o}nen, Mika and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter P and Kuusisto, Johanna and Launer, Lenore J and Li, Aihua and Linneberg, Allan and Luan, Jian{\textquoteright}an and Vidal, Pedro Marques and Medland, Sarah E and Milaneschi, Yuri and Moscati, Arden and Musk, Bill and Nelson, Christopher P and Nolte, Ilja M and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Power, Christine and Raitakari, Olli T and Reedik, M{\"a}gi and Reiner, Alex P and Ridker, Paul M and Rudan, Igor and Ryan, Kathy and Sarzynski, Mark A and Scott, Laura J and Scott, Robert A and Sidney, Stephen and Siggeirsdottir, Kristin and Smith, Albert V and Smith, Jennifer A and Sonestedt, Emily and Str{\o}m, Marin and Tai, E Shyong and Teo, Koon K and Thorand, Barbara and T{\"o}njes, Anke and Tremblay, Angelo and Uitterlinden, Andre G and Vangipurapu, Jagadish and van Schoor, Natasja and V{\"o}lker, Uwe and Willemsen, Gonneke and Williams, Kayleen and Wong, Quenna and Xu, Huichun and Young, Kristin L and Yuan, Jian Min and Zillikens, M Carola and Zonderman, Alan B and Ameur, Adam and Bandinelli, Stefania and Bis, Joshua C and Boehnke, Michael and Bouchard, Claude and Chasman, Daniel I and Smith, George Davey and de Geus, Eco J C and Deldicque, Louise and D{\"o}rr, Marcus and Evans, Michele K and Ferrucci, Luigi and Fornage, Myriam and Fox, Caroline and Garland, Jr, Theodore and Gudnason, Vilmundur and Gyllensten, Ulf and Hansen, Torben and Hayward, Caroline and Horta, Bernardo L and Hypponen, Elina and Jarvelin, Marjo-Riitta and Johnson, W Craig and Kardia, Sharon L R and Kiemeney, Lambertus A and Laakso, Markku and Langenberg, Claudia and Lehtim{\"a}ki, Terho and Marchand, Loic Le and Lifelines Cohort Study and Magnusson, Patrik K E and Martin, Nicholas G and Melbye, Mads and Metspalu, Andres and Meyre, David and North, Kari E and Ohlsson, Claes and Oldehinkel, Albertine J and Orho-Melander, Marju and Pare, Guillaume and Park, Taesung and Pedersen, Oluf and Penninx, Brenda W J H and Pers, Tune H and Polasek, Ozren and Prokopenko, Inga and Rotimi, Charles N and Samani, Nilesh J and Sim, Xueling and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Tim D and Timpson, Nicholas J and van Dam, Rob M and van der Velde, Nathalie and van Duijn, Cornelia M and Vollenweider, Peter and V{\"o}lzke, Henry and Voortman, Trudy and Waeber, G{\'e}rard and Wareham, Nicholas J and Weir, David R and Wichmann, Heinz-Erich and Wilson, James F and Hevener, Andrea L and Krook, Anna and Zierath, Juleen R and Thomis, Martine A I and Loos, Ruth J F and Hoed, Marcel den} } @article {460, title = {Genome-wide association meta-analysis identifies 29 new acne susceptibility loci}, journal = {Nature Communications}, volume = {13}, year = {2022}, pages = {702}, abstract = {

Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin. Severely inflamed lesions may leave permanent scars that have been associated with long-term psychosocial consequences. Here, we perform a GWAS meta-analysis comprising 20,165 individuals with acne from nine independent European ancestry cohorts. We identify 29 novel genome-wide significant loci and replicate 14 of the 17 previously identified risk loci, bringing the total number of reported acne risk loci to 46. Using fine-mapping and eQTL colocalisation approaches, we identify putative causal genes at several acne susceptibility loci that have previously been implicated in Mendelian hair and skin disorders, including pustular psoriasis. We identify shared genetic aetiology between acne, hormone levels, hormone-sensitive cancers and psychiatric traits. Finally, we show that a polygenic risk score calculated from our results explains up to 5.6\% of the variance in acne liability in an independent cohort.

}, doi = {10.1038/s41467-022-28252-5}, author = {Mitchell, Brittany L and Saklatvala, Jake R and Dand, Nick and Hagenbeek, Fiona A and Li, Xin and Min, Josine L and Thomas, Laurent and Bartels, Meike and Jan Hottenga, Jouke and Lupton, Michelle K and Boomsma, Dorret I and Dong, Xianjun and Hveem, Kristian and L{\o}set, Mari and Martin, Nicholas G and Barker, Jonathan N and Han, Jiali and Smith, Catherine H and Renter{\'\i}a, Miguel E and Simpson, Michael A} } @article {455, title = {Genome-wide association meta-analysis of childhood and adolescent internalizing symptoms}, journal = {Journal of the American Academy of Child \& Adolescent Psychiatry}, volume = {61}, year = {2022}, pages = {934{\textendash}945}, abstract = {

OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence.

METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.

RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66\%, 95\% CI = 0.84-2.48

}, keywords = {anxiety, Depression, genetic epidemiology, molecular genetics, repeated measures}, doi = {10.1016/j.jaac.2021.11.035}, author = {Jami, Eshim S and Hammerschlag, Anke R and Ip, Hill F and Allegrini, Andrea G and Benyamin, Beben and Border, Richard and Diemer, Elizabeth W and Jiang, Chang and Karhunen, Ville and Lu, Yi and Lu, Qing and Mallard, Travis T and Mishra, Pashupati P and Nolte, Ilja M and Palviainen, Teemu and Peterson, Roseann E and Sallis, Hannah M and Shabalin, Andrey A and Tate, Ashley E and Thiering, Elisabeth and Vilor-Tejedor, Nat{\`a}lia and Wang, Carol and Zhou, Ang and Adkins, Daniel E and Alemany, Silvia and Ask, Helga and Chen, Qi and Corley, Robin P and Ehli, Erik A and Evans, Luke M and Havdahl, Alexandra and Hagenbeek, Fiona A and Hakulinen, Christian and Henders, Anjali K and Hottenga, Jouke Jan and Korhonen, Tellervo and Mamun, Abdullah and Marrington, Shelby and Neumann, Alexander and Rimfeld, Kaili and Rivadeneira, Fernando and Silberg, Judy L and van Beijsterveldt, Catharina E and Vuoksimaa, Eero and Whipp, Alyce M and Tong, Xiaoran and Andreassen, Ole A and Boomsma, Dorret I and Brown, Sandra A and Burt, S Alexandra and Copeland, William and Dick, Danielle M and Harden, K Paige and Harris, Kathleen Mullan and Hartman, Catharina A and Heinrich, Joachim and Hewitt, John K and Hopfer, Christian and Hypponen, Elina and Jarvelin, Marjo-Riitta and Kaprio, Jaakko and Keltikangas-J{\"a}rvinen, Liisa and Klump, Kelly L and Krauter, Kenneth and Kuja-Halkola, Ralf and Larsson, Henrik and Lehtim{\"a}ki, Terho and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Maes, Hermine H and Magnus, Per and Munaf{\`o}, Marcus R and Najman, Jake M and Nj{\o}lstad, P\aal R and Oldehinkel, Albertine J and Pennell, Craig E and Plomin, Robert and Reichborn-Kjennerud, Ted and Reynolds, Chandra and Rose, Richard J and Smolen, Andrew and Snieder, Harold and Stallings, Michael and Standl, Marie and Sunyer, Jordi and Tiemeier, Henning and Wadsworth, Sally J and Wall, Tamara L and Whitehouse, Andrew J O and Williams, Gail M and Ystr{\o}m, Eivind and Nivard, Michel G and Bartels, Meike and Middeldorp, Christel M} } @article {462, title = {Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities}, journal = {Translational Psychiatry}, volume = {12}, year = {2022}, pages = {495}, abstract = {

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)\–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n\ =\ 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45\ \×\ 10\–2, threshold = 2.5\ \×\ 10\–2). For the GenLang Cohort (n\ =\ 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q\ =\ 1.02\ \×\ 10\–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n\ =\ 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q\ \<\ 9.00\ \×\ 10\–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

}, doi = {10.1038/s41398-022-02250-z}, author = {Price, Kaitlyn M and Wigg, Karen G and Eising, Else and Feng, Yu and Blokland, Kirsten and Wilkinson, Margaret and Kerr, Elizabeth N and Guger, Sharon L and Quantitative Trait Working Group of the GenLang Consortium and Fisher, Simon E and Lovett, Maureen W and Strug, Lisa J and Barr, Cathy L} } @article {461, title = {Item-level genome-wide association study of the Alcohol Use Disorders Identification Test in three population-based cohorts}, journal = {The American Journal of Psychiatry}, volume = {179}, year = {2022}, pages = {58{\textendash}70}, abstract = {

OBJECTIVE: Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.

METHODS: To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.

RESULTS: The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ({\textquoteleft}{\textquoteleft}consumption\&$\#$39;\&$\#$39; and {\textquoteleft}{\textquoteleft}problems,\&$\#$39;\&$\#$39; rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.

CONCLUSIONS: This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

}, keywords = {Alcohol, Alcohol Consumption, ALSPAC, Genomic Structural Equation Modeling, GWAS, Substance-Related and Addictive Disorders}, doi = {10.1176/appi.ajp.2020.20091390}, author = {Mallard, Travis T and Savage, Jeanne E and Johnson, Emma C and Huang, Yuye and Edwards, Alexis C and Hottenga, Jouke J and Grotzinger, Andrew D and Gustavson, Daniel E and Jennings, Mariela V and Anokhin, Andrey and Dick, Danielle M and Edenberg, Howard J and Kramer, John R and Lai, Dongbing and Meyers, Jacquelyn L and Pandey, Ashwini K and Harden, Kathryn Paige and Nivard, Michel G and de Geus, Eco J C and Boomsma, Dorret I and Agrawal, Arpana and Davis, Lea K and Clarke, Toni-Kim and Palmer, Abraham A and Sanchez-Roige, Sandra} } @article {465, title = {Overview of CAPICE - Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe - an EU Marie Sk{\l}odowska-Curie International Training Network}, journal = {European Child \& Adolescent Psychiatry}, volume = {31}, year = {2022}, pages = {829{\textendash}839}, abstract = {

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).

}, keywords = {anxiety, Attention deficit hyperactivity disorder (ADHD), Childhood and adolescence psychopathology, Depression, Psychiatric genetics}, doi = {10.1007/s00787-020-01713-2}, author = {Rajula, Hema Sekhar Reddy and Manchia, Mirko and Agarwal, Kratika and Akingbuwa, Wonuola A and Allegrini, Andrea G and Diemer, Elizabeth and Doering, Sabrina and Haan, Elis and Jami, Eshim S and Karhunen, Ville and Leone, Marica and Schellhas, Laura and Thompson, Ashley and van den Berg, St{\'e}phanie M and Bergen, Sarah E and Kuja-Halkola, Ralf and Hammerschlag, Anke R and J{\"a}rvelin, Marjo Riitta and Leval, Amy and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Mauri, Matteo and Munaf{\`o}, Marcus R and Myers, David and Plomin, Robert and Rimfeld, Kaili and Tiemeier, Henning and Ystrom, Eivind and Fanos, Vassilios and Bartels, Meike and Middeldorp, Christel M} } @article {454, title = {1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans}, journal = {Translational Psychiatry}, volume = {11}, year = {2021}, pages = {182}, abstract = {

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48\% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

}, doi = { 10.1038/s41398-021-01213-0}, author = {S{\o}nderby, Ida E and van der Meer, Dennis and Moreau, Clara and Kaufmann, Tobias and Walters, G Bragi and Ellegaard, Maria and Abdellaoui, Abdel and Ames, David and Amunts, Katrin and Andersson, Micael and Armstrong, Nicola J and Bernard, Manon and Blackburn, Nicholas B and Blangero, John and Boomsma, Dorret I and Brodaty, Henry and Brouwer, Rachel M and B{\"u}low, Robin and B{\o}en, Rune and Cahn, Wiepke and Calhoun, Vince D and Caspers, Svenja and Ching, Christopher R K and Cichon, Sven and Ciufolini, Simone and Crespo-Facorro, Benedicto and Curran, Joanne E and Dale, Anders M and Dalvie, Shareefa and Dazzan, Paola and de Geus, Eco J C and de Zubicaray, Greig I and de Zwarte, Sonja M C and Desrivieres, Sylvane and Doherty, Joanne L and Donohoe, Gary and Draganski, Bogdan and Ehrlich, Stefan and Eising, Else and Espeseth, Thomas and Fejgin, Kim and Fisher, Simon E and Fladby, Tormod and Frei, Oleksandr and Frouin, Vincent and Fukunaga, Masaki and Gareau, Thomas and Ge, Tian and Glahn, David C and Grabe, Hans J and Groenewold, Nynke A and G{\'u}stafsson, {\'O}mar and Haavik, Jan and Haberg, Asta K and Hall, Jeremy and Hashimoto, Ryota and Hehir-Kwa, Jayne Y and Hibar, Derrek P and Hillegers, Manon H J and Hoffmann, Per and Holleran, Laurena and Holmes, Avram J and Homuth, Georg and Hottenga, Jouke-Jan and Hulshoff Pol, Hilleke E and Ikeda, Masashi and Jahanshad, Neda and Jockwitz, Christiane and Johansson, Stefan and J{\"o}nsson, Erik G and J{\o}rgensen, Niklas R and Kikuchi, Masataka and Knowles, Emma E M and Kumar, Kuldeep and Le Hellard, Stephanie and Leu, Costin and Linden, David E J and Liu, Jingyu and Lundervold, Arvid and Lundervold, Astri Johansen and Maillard, Anne M and Martin, Nicholas G and Martin-Brevet, Sandra and Mather, Karen A and Mathias, Samuel R and McMahon, Katie L and McRae, Allan F and Medland, Sarah E and Meyer-Lindenberg, Andreas and Moberget, Torgeir and Modenato, Claudia and S{\'a}nchez, Jennifer Monereo and Morris, Derek W and M{\"u}hleisen, Thomas W and Murray, Robin M and Nielsen, Jacob and Nordvik, Jan E and Nyberg, Lars and Loohuis, Loes M Olde and Ophoff, Roel A and Owen, Michael J and Paus, Tomas and Pausova, Zdenka and Peralta, Juan M and Pike, G Bruce and Prieto, Carlos and Quinlan, Erin B and Reinbold, C{\'e}line S and Marques, Tiago Reis and Rucker, James J H and Sachdev, Perminder S and Sando, Sigrid B and Schofield, Peter R and Schork, Andrew J and Schumann, Gunter and Shin, Jean and Shumskaya, Elena and Silva, Ana I and Sisodiya, Sanjay M and Steen, Vidar M and Stein, Dan J and Strike, Lachlan T and Suzuki, Ikuo K and Tamnes, Christian K and Teumer, Alexander and Thalamuthu, Anbupalam and Tordesillas-Guti{\'e}rrez, Diana and Uhlmann, Anne and Ulfarsson, Magnus O and van {\textquoteright}t Ent, Dennis and van den Bree, Marianne B M and Vanderhaeghen, Pierre and Vassos, Evangelos and Wen, Wei and Wittfeld, Katharina and Wright, Margaret J and Agartz, Ingrid and Djurovic, Srdjan and Westlye, Lars T and Stefansson, Hreinn and Stefansson, Kari and Jacquemont, S{\'e}bastien and Thompson, Paul M and Andreassen, Ole A and ENIGMA-CNV working group} } @inbook {444, title = {Chapter 13 - Combining twin-family designs with measured genetic variants to study the causes of epigenetic variation}, booktitle = {Twin and Family Studies of Epigenetics}, series = {Translational Epigenetics}, volume = {27}, year = {2021}, pages = {239-259}, publisher = {Academic Press}, organization = {Academic Press}, abstract = {

Classical twin and family designs can be applied to examine the contribution of genetic and environmental influences to variation in epigenetic marks. Such models can be extended to allow for more in-depth questions, such as: How much of the variation in DNA methylation is explained by methylation Quantitative Trait Loci (QTLs)? Does the contribution of genetic or environmental influences differ between males and females or between younger and older individuals? Does methylation level at CpG site X have a causal effect on trait Y and vice versa, or is the association driven by genetic pleiotropy? In this chapter, we discuss twin designs that allow to address these questions. First, we describe models that incorporate genetic relationships based on genome-wide SNP data and the application of such models to DNA methylation data from adult twins and family members. Second, we discuss the value of an integration of Mendelian Randomization (MR) with the classical twin design.

}, keywords = {Causality, Direction of causation (DOC), DNA methylation, epigenetics, Genetic relatedness matrix (GRM), heritability, Mendelian Randomization (MR), Mendelian Randomization{\textemdash}direction of causation model (MR-DoC), Single nucleotide polymorphism (SNP) heritability, twins}, isbn = {978-0-12-820951-6}, doi = {https://doi.org/10.1016/B978-0-12-820951-6.00007-7}, url = {https://www.sciencedirect.com/science/article/pii/B9780128209516000077}, author = {Camelia C. Minic{\u a} and Michael C. Neale and Dorret I. Boomsma and Jenny van Dongen}, editor = {Shuai Li and John L. Hopper} } @inbook {438, title = {Chapter 3 - Discordant monozygotic twin studies of epigenetic mechanisms in mental health}, booktitle = {Twin and Family Studies of Epigenetics}, series = {Translational Epigenetics}, volume = {27}, year = {2021}, pages = {43-66}, publisher = {Academic Press}, organization = {Academic Press}, abstract = {

The discordant monozygotic twin design is a strong method to assess causality. The design has been applied in a number of studies to investigate epigenetic mechanisms associated with mental health. These studies initially mainly focused on candidate genes and increasingly on genome-wide DNA methylation, gene expression, and X-chromosome inactivation, in various surrogate tissues such as blood and buccal cells, but also in brain tissue. In this chapter we review monozygotic twin studies of autism, aggressive behavior, ADHD, schizophrenia, bipolar disorder, and depression. We discuss the insights obtained by these studies and describe current limitations and challenges, including sample size, the use of surrogate tissues, causality, and confounders that apply to studies of cognitive and mental health such as medication use, lifestyle, and cellular heterogeneity of commonly investigated tissues.

}, keywords = {ADHD, Aggressive Behavior, Autism, Bipolar disorder, Depression, Discordant, epigenetics, Schizophrenia, twins}, isbn = {978-0-12-820951-6}, doi = {https://doi.org/10.1016/B978-0-12-820951-6.00003-X}, url = {https://www.sciencedirect.com/science/article/pii/B978012820951600003X}, author = {Jenny van Dongen and Veronika V. Odintsova and Dorret I. Boomsma}, editor = {Shuai Li and John L. Hopper} } @article {439, title = {DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan}, journal = {Molecular Psychiatry}, volume = {26}, year = {2021}, pages = {2148{\textendash}2162}, abstract = {

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 $\times$ 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83\% of these sites showed the same direction of association with childhood aggression (r = 0.7

}, doi = {10.1038/s41380-020-00987-x}, author = {van Dongen, Jenny and Hagenbeek, Fiona A and Suderman, Matthew and Roetman, Peter J and Sugden, Karen and Chiocchetti, Andreas G and Ismail, Khadeeja and Mulder, Rosa H and Hafferty, Jonathan D and Adams, Mark J and Walker, Rosie M and Morris, Stewart W and Lahti, Jari and K{\"u}pers, Leanne K and Escaramis, Georgia and Alemany, Silvia and Jan Bonder, Marc and Meijer, Mandy and Ip, Hill F and Jansen, Rick and Baselmans, Bart M L and Parmar, Priyanka and Lowry, Estelle and Streit, Fabian and Sirignano, Lea and Send, Tabea S and Frank, Josef and Jylh{\"a}v{\"a}, Juulia and Wang, Yunzhang and Mishra, Pashupati Prasad and Colins, Olivier F and Corcoran, David L and Poulton, Richie and Mill, Jonathan and Hannon, Eilis and Arseneault, Louise and Korhonen, Tellervo and Vuoksimaa, Eero and Felix, Janine F and Bakermans-Kranenburg, Marian J and Campbell, Archie and Czamara, Darina and Binder, Elisabeth and Corpeleijn, Eva and Gonzalez, Juan R and Grazuleviciene, Regina and Gutzkow, Kristine B and Evandt, Jorunn and Vafeiadi, Marina and Klein, Marieke and van der Meer, Dennis and Ligthart, Lannie and BIOS Consortium and Kluft, Cornelis and Davies, Gareth E and Hakulinen, Christian and Keltikangas-J{\"a}rvinen, Liisa and Franke, Barbara and Freitag, Christine M and Konrad, Kerstin and Hervas, Amaia and Fern{\'a}ndez-Rivas, Aranzazu and Vetro, Agnes and Raitakari, Olli and Lehtim{\"a}ki, Terho and Vermeiren, Robert and Strandberg, Timo and R{\"a}ikk{\"o}nen, Katri and Snieder, Harold and Witt, Stephanie H and Deuschle, Michael and Pedersen, Nancy L and H{\"a}gg, Sara and Sunyer, Jordi and Franke, Lude and Kaprio, Jaakko and Ollikainen, Miina and Moffitt, Terrie E and Tiemeier, Henning and van IJzendoorn, Marinus H and Relton, Caroline and Vrijheid, Martine and Sebert, Sylvain and Jarvelin, Marjo-Riitta and Caspi, Avshalom and Evans, Kathryn L and McIntosh, Andrew M and Bartels, Meike and Boomsma, Dorret I} } @article {437, title = {Genetic association study of childhood aggression across raters, instruments, and age}, journal = {Translational Psychiatry}, volume = {11}, year = {2021}, pages = {413}, abstract = {

Childhood aggressive behavior (AGG) has a substantial heritability of around 50\%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31\% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44\%) and in retrospectively assessed childhood aggression (variance explained = 0.20\%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = \ -0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

}, doi = {10.1038/s41398-021-01480-x}, author = {Ip, Hill F and Van der Laan, Camiel M and Krapohl, Eva M L and Brikell, Isabell and S{\'a}nchez-Mora, Cristina and Nolte, Ilja M and St Pourcain, Beate and Bolhuis, Koen and Palviainen, Teemu and Zafarmand, Hadi and Colodro-Conde, Luc{\'\i}a and Gordon, Scott and Zayats, Tetyana and Aliev, Fazil and Jiang, Chang and Wang, Carol A and Saunders, Gretchen and Karhunen, Ville and Hammerschlag, Anke R and Adkins, Daniel E and Border, Richard and Peterson, Roseann E and Prinz, Joseph A and Thiering, Elisabeth and Sepp{\"a}l{\"a}, Ilkka and Vilor-Tejedor, Nat{\`a}lia and Ahluwalia, Tarunveer S and Day, Felix R and Hottenga, Jouke-Jan and Allegrini, Andrea G and Rimfeld, Kaili and Chen, Qi and Lu, Yi and Martin, Joanna and Soler Artigas, Mar{\'\i}a and Rovira, Paula and Bosch, Rosa and Espa{\~n}ol, Gemma and Ramos Quiroga, Josep Antoni and Neumann, Alexander and Ensink, Judith and Grasby, Katrina and Morosoli, Jos{\'e} J and Tong, Xiaoran and Marrington, Shelby and Middeldorp, Christel and Scott, James G and Vinkhuyzen, Anna and Shabalin, Andrey A and Corley, Robin and Evans, Luke M and Sugden, Karen and Alemany, Silvia and Sass, L{\ae}rke and Vinding, Rebecca and Ruth, Kate and Tyrrell, Jess and Davies, Gareth E and Ehli, Erik A and Hagenbeek, Fiona A and de Zeeuw, Eveline and van Beijsterveldt, Toos C E M and Larsson, Henrik and Snieder, Harold and Verhulst, Frank C and Amin, Najaf and Whipp, Alyce M and Korhonen, Tellervo and Vuoksimaa, Eero and Rose, Richard J and Uitterlinden, Andre G and Heath, Andrew C and Madden, Pamela and Haavik, Jan and Harris, Jennifer R and Helgeland, {\O}yvind and Johansson, Stefan and Knudsen, Gun Peggy S and Njolstad, Pal Rasmus and Lu, Qing and Rodriguez, Alina and Henders, Anjali K and Mamun, Abdullah and Najman, Jackob M and Brown, Sandy and Hopfer, Christian and Krauter, Kenneth and Reynolds, Chandra and Smolen, Andrew and Stallings, Michael and Wadsworth, Sally and Wall, Tamara L and Silberg, Judy L and Miller, Allison and Keltikangas-J{\"a}rvinen, Liisa and Hakulinen, Christian and Pulkki-R\aaback, Laura and Havdahl, Alexandra and Magnus, Per and Raitakari, Olli T and Perry, John R B and Llop, Sabrina and Lopez-Espinosa, Maria-Jose and B{\o}nnelykke, Klaus and Bisgaard, Hans and Sunyer, Jordi and Lehtim{\"a}ki, Terho and Arseneault, Louise and Standl, Marie and Heinrich, Joachim and Boden, Joseph and Pearson, John and Horwood, L John and Kennedy, Martin and Poulton, Richie and Eaves, Lindon J and Maes, Hermine H and Hewitt, John and Copeland, William E and Costello, Elizabeth J and Williams, Gail M and Wray, Naomi and Jarvelin, Marjo-Riitta and McGue, Matt and Iacono, William and Caspi, Avshalom and Moffitt, Terrie E and Whitehouse, Andrew and Pennell, Craig E and Klump, Kelly L and Burt, S Alexandra and Dick, Danielle M and Reichborn-Kjennerud, Ted and Martin, Nicholas G and Medland, Sarah E and Vrijkotte, Tanja and Kaprio, Jaakko and Tiemeier, Henning and Davey Smith, George and Hartman, Catharina A and Oldehinkel, Albertine J and Casas, Miquel and Ribas{\'e}s, Marta and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Plomin, Robert and Bartels, Meike and Nivard, Michel G and Boomsma, Dorret I} } @article {433, title = {Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight}, journal = {Human Molecular Genetics}, volume = {30}, year = {2021}, pages = {1894{\textendash}1905}, abstract = {

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson\&$\#$39;s r = 0.66, 95\% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95\% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.

}, doi = {10.1093/hmg/ddab121}, author = {Beck, Jeffrey J and Pool, Ren{\'e} and van de Weijer, Margot and Chen, Xu and Krapohl, Eva and Gordon, Scott D and Nygaard, Marianne and Debrabant, Birgit and Palviainen, Teemu and van der Zee, Matthijs D and Baselmans, Bart and Finnicum, Casey T and Yi, Lu and Lundstr{\"o}m, Sebastian and van Beijsterveldt, Toos and Christiansen, Lene and Heikkil{\"a}, Kauko and Kittelsrud, Julie and Loukola, Anu and Ollikainen, Miina and Christensen, Kaare and Martin, Nicholas G and Plomin, Robert and Nivard, Michel and Bartels, Meike and Dolan, Conor and Willemsen, Gonneke and de Geus, Eco and Almqvist, Catarina and Magnusson, Patrik K E and Mbarek, Hamdi and Ehli, Erik A and Boomsma, Dorret I and Hottenga, Jouke-Jan} } @article {442, title = {The heritability of Type D personality by an extended twin-pedigree analysis in the Netherlands Twin Register}, journal = {Behavior Genetics}, volume = {51}, year = {2021}, pages = {1{\textendash}11}, abstract = {

Type D (Distressed) personality combines negative affectivity (NA) and social inhibition (SI) and is associated with an increased risk of cardiovascular disease. We aimed to (1) validate a new proxy based on the Achenbach System of Empirically Based Assessment (ASEBA) for Type D personality and its NA and SI subcomponents and (2) estimate the heritability of the Type D proxy in an extended twin-pedigree design in the Netherlands Twin Register (NTR). Proxies for the dichotomous Type D classification, and continuous NA, SI, and NAxSI (the continuous measure of Type D) scales were created based on 12 ASEBA items for 30,433 NTR participants (16,449 twins and 13,984 relatives from 11,106 pedigrees) and sources of variation were analyzed in the \&$\#$39;Mendel\&$\#$39; software package. We estimated additive and non-additive genetic variance components, shared household and unique environmental variance components and ran bivariate models to estimate the genetic and non-genetic covariance between NA and SI. The Type D proxy showed good reliability and construct validity. The best fitting genetic model included additive and non-additive genetic effects with broad-sense heritabilities for NA, SI and NAxSI estimated at 49\%, 50\% and 49\%, respectively. Household effects showed small contributions (4-9\%) to the total phenotypic variation. The genetic correlation between NA and SI was .66 (reflecting both additive and non-additive genetic components). Thus, Type D personality and its NA and SI subcomponents are heritable, with a shared genetic basis for the two subcomponents.

}, keywords = {Extended twin-family design, Genetic non-additivity, heritability, Negative affectivity, Netherlands Twin Register, Pedigree analysis, Shared household effect, Social inhibition, Type D personality}, doi = {10.1007/s10519-020-10023-x}, author = {Li-Gao, Ruifang and Boomsma, Dorret I and de Geus, Eco J C and Denollet, Johan and Kupper, Nina} } @article {428, title = {Higher aggression is related to poorer academic performance in compulsory education}, journal = {Journal of Child Psychology and Psychiatry}, volume = {62}, year = {2021}, pages = {327{\textendash}338}, abstract = {

BACKGROUND: To conduct a comprehensive assessment of the association between aggression and academic performance in compulsory education.

METHOD: We studied aggression and academic performance in over 27,000 individuals from four European twin cohorts participating in the ACTION consortium (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies). Individual level data on aggression at ages 7-16 were assessed by three instruments (Achenbach System of Empirically Based Assessment, Multidimensional Peer Nomination Inventory, Strengths and Difficulties Questionnaire) including parental, teacher and self-reports. Academic performance was measured with teacher-rated grade point averages (ages 12-14) or standardized test scores (ages 12-16). Random effect meta-analytical correlations with academic performance were estimated for parental ratings (in all four cohorts) and self-ratings (in three cohorts).

RESULTS: All between-family analyses indicated significant negative aggression-academic performance associations with correlations ranging from -.06 to -.33. Results were similar across different ages, instruments and raters and either with teacher-rated grade point averages or standardized test scores as measures of academic performance. Meta-analytical r\&$\#$39;s were -.20 and -.23 for parental and self-ratings, respectively. In within-family analyses of all twin pairs, the negative aggression-academic performance associations were statistically significant in 14 out of 17 analyses (r = -.17 for parental- and r = -.16 for self-ratings). Separate analyses in monozygotic (r = -.07 for parental and self-ratings), same-sex dizygotic (r\&$\#$39;s = -.16 and -.17 for parental and self-ratings) and opposite-sex dizygotic (r\&$\#$39;s = -.21 and -.19 for parental and self-ratings) twin pairs suggested partial confounding by genetic effects.

CONCLUSIONS: There is a robust negative association between aggression and academic performance in compulsory education. Part of these associations were explained by shared genetic effects, but some evidence of a negative association between aggression and academic performance remained even in within-family analyses of monozygotic twin pairs.

}, keywords = {Aggression, cognition, development, educational attainment, school performance}, doi = {10.1111/jcpp.13273}, author = {Vuoksimaa, Eero and Rose, Richard J and Pulkkinen, Lea and Palviainen, Teemu and Rimfeld, Kaili and Lundstr{\"o}m, Sebastian and Bartels, Meike and van Beijsterveldt, Catharina and Hendriks, Anne and de Zeeuw, Eveline L and Plomin, Robert and Lichtenstein, Paul and Boomsma, Dorret I and Kaprio, Jaakko} } @article {449, title = {Higher aggression is related to poorer academic performance in compulsory education}, journal = {Journal of Child Psychology and Psychiatry}, volume = {62}, year = {2021}, pages = {327{\textendash}338}, abstract = {

BACKGROUND: To conduct a comprehensive assessment of the association between aggression and academic performance in compulsory education.

METHOD: We studied aggression and academic performance in over 27,000 individuals from four European twin cohorts participating in the ACTION consortium (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies). Individual level data on aggression at ages 7-16 were assessed by three instruments (Achenbach System of Empirically Based Assessment, Multidimensional Peer Nomination Inventory, Strengths and Difficulties Questionnaire) including parental, teacher and self-reports. Academic performance was measured with teacher-rated grade point averages (ages 12-14) or standardized test scores (ages 12-16). Random effect meta-analytical correlations with academic performance were estimated for parental ratings (in all four cohorts) and self-ratings (in three cohorts).

RESULTS: All between-family analyses indicated significant negative aggression-academic performance associations with correlations ranging from -.06 to -.33. Results were similar across different ages, instruments and raters and either with teacher-rated grade point averages or standardized test scores as measures of academic performance. Meta-analytical r\&$\#$39;s were -.20 and -.23 for parental and self-ratings, respectively. In within-family analyses of all twin pairs, the negative aggression-academic performance associations were statistically significant in 14 out of 17 analyses (r = -.17 for parental- and r = -.16 for self-ratings). Separate analyses in monozygotic (r = -.07 for parental and self-ratings), same-sex dizygotic (r\&$\#$39;s = -.16 and -.17 for parental and self-ratings) and opposite-sex dizygotic (r\&$\#$39;s = -.21 and -.19 for parental and self-ratings) twin pairs suggested partial confounding by genetic effects.

CONCLUSIONS: There is a robust negative association between aggression and academic performance in compulsory education. Part of these associations were explained by shared genetic effects, but some evidence of a negative association between aggression and academic performance remained even in within-family analyses of monozygotic twin pairs.

}, keywords = {Aggression, cognition, development, educational attainment, school performance}, doi = {10.1111/jcpp.13273}, author = {Vuoksimaa, Eero and Rose, Richard J and Pulkkinen, Lea and Palviainen, Teemu and Rimfeld, Kaili and Lundstr{\"o}m, Sebastian and Bartels, Meike and van Beijsterveldt, Catharina and Hendriks, Anne and de Zeeuw, Eveline L and Plomin, Robert and Lichtenstein, Paul and Boomsma, Dorret I and Kaprio, Jaakko} } @article {440, title = {Identical twins carry a persistent epigenetic signature of early genome programming}, journal = {Nature Communications}, volume = {12}, year = {2021}, pages = {5618}, abstract = {

Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.

}, doi = {10.1038/s41467-021-25583-7}, author = {van Dongen, Jenny and Gordon, Scott D and McRae, Allan F and Odintsova, Veronika V and Mbarek, Hamdi and Breeze, Charles E and Sugden, Karen and Lundgren, Sara and Castillo-Fernandez, Juan E and Hannon, Eilis and Moffitt, Terrie E and Hagenbeek, Fiona A and van Beijsterveldt, Catharina E M and Jan Hottenga, Jouke and Tsai, Pei-Chien and BIOS Consortium and Genetics of DNA Methylation Consortium and Min, Josine L and Hemani, Gibran and Ehli, Erik A and Paul, Franziska and Stern, Claudio D and Heijmans, Bastiaan T and Slagboom, P Eline and Daxinger, Lucia and van der Maarel, Silv{\`e}re M and de Geus, Eco J C and Willemsen, Gonneke and Montgomery, Grant W and Reversade, Bruno and Ollikainen, Miina and Kaprio, Jaakko and Spector, Tim D and Bell, Jordana T and Mill, Jonathan and Caspi, Avshalom and Martin, Nicholas G and Boomsma, Dorret I} } @article {452, title = {Ketone body 3-hydroxybutyrate as a biomarker of aggression}, journal = {Nature Scientific Reports}, volume = {11}, year = {2021}, pages = {5813}, abstract = {

Human aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983-1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one-3-hydroxybutyrate, a ketone body produced during fasting-showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

}, doi = {10.1038/s41598-021-84635-6}, author = {Whipp, A M and Vuoksimaa, E and Korhonen, T and Pool, R and But, A and Ligthart, L and Hagenbeek, F A and Bartels, M and Bogl, L H and Pulkkinen, L and Rose, R J and Boomsma, D I and Kaprio, J} } @article {436, title = {Large-scale association analyses identify host factors influencing human gut microbiome composition}, journal = {Nature Genetics}, volume = {53}, year = {2021}, pages = {156{\textendash}165}, abstract = {

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95\% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P \< 5 $\times$ 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 $\times$ 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 $\times$ 10-10 \< P \< 5 $\times$ 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

}, doi = {10.1038/s41588-020-00763-1}, author = {Kurilshikov, Alexander and Medina-Gomez, Carolina and Bacigalupe, Rodrigo and Radjabzadeh, Djawad and Wang, Jun and Demirkan, Ayse and Le Roy, Caroline I and Raygoza Garay, Juan Antonio and Finnicum, Casey T and Liu, Xingrong and Zhernakova, Daria V and Bonder, Marc Jan and Hansen, Tue H and Frost, Fabian and R{\"u}hlemann, Malte C and Turpin, Williams and Moon, Jee-Young and Kim, Han-Na and L{\"u}ll, Kreete and Barkan, Elad and Shah, Shiraz A and Fornage, Myriam and Szopinska-Tokov, Joanna and Wallen, Zachary D and Borisevich, Dmitrii and Agreus, Lars and Andreasson, Anna and Bang, Corinna and Bedrani, Larbi and Bell, Jordana T and Bisgaard, Hans and Boehnke, Michael and Boomsma, Dorret I and Burk, Robert D and Claringbould, Annique and Croitoru, Kenneth and Davies, Gareth E and van Duijn, Cornelia M and Duijts, Liesbeth and Falony, Gwen and Fu, Jingyuan and van der Graaf, Adriaan and Hansen, Torben and Homuth, Georg and Hughes, David A and Ijzerman, Richard G and Jackson, Matthew A and Jaddoe, Vincent W V and Joossens, Marie and J{\o}rgensen, Torben and Keszthelyi, Daniel and Knight, Rob and Laakso, Markku and Laudes, Matthias and Launer, Lenore J and Lieb, Wolfgang and Lusis, Aldons J and Masclee, Ad A M and Moll, Henriette A and Mujagic, Zlatan and Qibin, Qi and Rothschild, Daphna and Shin, Hocheol and S{\o}rensen, S{\o}ren J and Steves, Claire J and Thorsen, Jonathan and Timpson, Nicholas J and Tito, Raul Y and Vieira-Silva, Sara and V{\"o}lker, Uwe and V{\"o}lzke, Henry and V{\~o}sa, Urmo and Wade, Kaitlin H and Walter, Susanna and Watanabe, Kyoko and Weiss, Stefan and Weiss, Frank U and Weissbrod, Omer and Westra, Harm-Jan and Willemsen, Gonneke and Payami, Haydeh and Jonkers, Daisy M A E and Arias Vasquez, Alejandro and de Geus, Eco J C and Meyer, Katie A and Stokholm, Jakob and Segal, Eran and Org, Elin and Wijmenga, Cisca and Kim, Hyung-Lae and Kaplan, Robert C and Spector, Tim D and Uitterlinden, Andre G and Rivadeneira, Fernando and Franke, Andre and Lerch, Markus M and Franke, Lude and Sanna, Serena and D{\textquoteright}Amato, Mauro and Pedersen, Oluf and Paterson, Andrew D and Kraaij, Robert and Raes, Jeroen and Zhernakova, Alexandra} } @article {445, title = {Large-scale collaboration in ENIGMA-EEG: A perspective on the meta-analytic approach to link neurological and psychiatric liability genes to electrophysiological brain activity}, journal = {Brain and Behavior}, volume = {11}, year = {2021}, pages = {e02188}, abstract = {

BACKGROUND AND PURPOSE: The ENIGMA-EEG working group was established to enable large-scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain.

METHODS: We summarize how we have performed our currently largest genome-wide association study of oscillatory brain activity in EEG recordings by meta-analyzing the results across five participating cohorts, resulting in the first genome-wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta-analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations.

RESULTS: We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters.

CONCLUSION: The long list of potential challenges to our large-scale meta-analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability.

}, keywords = {brain disorders, electroencephalography, ENIGMA, harmonization, imaging genetics, open science}, doi = {10.1002/brb3.2188}, author = {Smit, Dirk J A and Andreassen, Ole A and Boomsma, Dorret I and Burwell, Scott J and Chorlian, David B and de Geus, Eco J C and Elvs\aashagen, Torbj{\o}rn and Gordon, Reyna L and Harper, Jeremy and Hegerl, Ulrich and Hensch, Tilman and Iacono, William G and Jawinski, Philippe and J{\"o}nsson, Erik G and Luykx, Jurjen J and Magne, Cyrille L and Malone, Stephen M and Medland, Sarah E and Meyers, Jacquelyn L and Moberget, Torgeir and Porjesz, Bernice and Sander, Christian and Sisodiya, Sanjay M and Thompson, Paul M and van Beijsterveldt, Catharina E M and van Dellen, Edwin and Via, Marc and Wright, Margaret J} } @article {446, title = {Predicting complex traits and exposures from polygenic scores and blood and buccal DNA methylation profiles}, journal = {Frontiers in Psychiatry}, volume = {12}, year = {2021}, pages = {688464}, abstract = {

We examined the performance of methylation scores (MS) and polygenic scores (PGS) for birth weight, BMI, prenatal maternal smoking exposure, and smoking status to assess the extent to which MS could predict these traits and exposures over and above the PGS in a multi-omics prediction model. MS may be seen as the epigenetic equivalent of PGS, but because of their dynamic nature and sensitivity of non-genetic exposures may add to complex trait prediction independently of PGS. MS and PGS were calculated based on genotype data and DNA-methylation data in blood samples from adults (Illumina 450 K; N = 2,431; mean age 35.6) and in buccal samples from children (Illumina EPIC; N = 1,128; mean age 9.6) from the Netherlands Twin Register. Weights to construct the scores were obtained from results of large epigenome-wide association studies (EWASs) based on whole blood or cord blood methylation data and genome-wide association studies (GWASs). In adults, MSs in blood predicted independently from PGSs, and outperformed PGSs for BMI, prenatal maternal smoking, and smoking status, but not for birth weight. The largest amount of variance explained by the multi-omics prediction model was for current vs. never smoking (54.6\%) of which 54.4\% was captured by the MS. The two predictors captured 16\% of former vs. never smoking initiation variance (MS:15.5\%, PGS: 0.5\%), 17.7\% of prenatal maternal smoking variance (MS:16.9\%, PGS: 0.8\%), 11.9\% of BMI variance (MS: 6.4\%, PGS 5.5\%), and 1.9\% of birth weight variance (MS: 0.4\%, PGS: 1.5\%). In children, MSs in buccal samples did not show independent predictive value. The largest amount of variance explained by the two predictors was for prenatal maternal smoking (2.6\%), where the MSs contributed 1.5\%. These results demonstrate that blood DNA MS in adults explain substantial variance in current smoking, large variance in former smoking, prenatal smoking, and BMI, but not in birth weight. Buccal cell DNA methylation scores have lower predictive value, which could be due to different tissues in the EWAS discovery studies and target sample, as well as to different ages. This study illustrates the value of combining polygenic scores with information from methylation data for complex traits and exposure prediction.

}, keywords = {birth weight, BMI, DNA methylation, maternal smoking, methylation scores, multi-omics prediction, polygenic scores, smoking}, doi = {10.3389/fpsyt.2021.688464}, author = {Odintsova, Veronika V and Rebattu, Valerie and Hagenbeek, Fiona A and Pool, Ren{\'e} and Beck, Jeffrey J and Ehli, Erik A and van Beijsterveldt, Catharina E M and Ligthart, Lannie and Willemsen, Gonneke and de Geus, Eco J C and Hottenga, Jouke-Jan and Boomsma, Dorret I and van Dongen, Jenny} } @article {443, title = {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability}, journal = {Nature Communications}, volume = {12}, year = {2021}, pages = {24}, abstract = {

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

}, doi = {10.1038/s41467-020-19366-9}, author = {Lagou, Vasiliki and M{\"a}gi, Reedik and Hottenga, Jouke- Jan and Grallert, Harald and Perry, John R B and Bouatia-Naji, Nabila and Marullo, Letizia and Rybin, Denis and Jansen, Rick and Min, Josine L and Dimas, Antigone S and Ulrich, Anna and Zudina, Liudmila and G\aadin, Jesper R and Jiang, Longda and Faggian, Alessia and Bonnefond, Am{\'e}lie and Fadista, Joao and Stathopoulou, Maria G and Isaacs, Aaron and Willems, Sara M and Navarro, Pau and Tanaka, Toshiko and Jackson, Anne U and Montasser, May E and O{\textquoteright}Connell, Jeff R and Bielak, Lawrence F and Webster, Rebecca J and Saxena, Richa and Stafford, Jeanette M and Pourcain, Beate St and Timpson, Nicholas J and Salo, Perttu and Shin, So-Youn and Amin, Najaf and Smith, Albert V and Li, Guo and Verweij, Niek and Goel, Anuj and Ford, Ian and Johnson, Paul C D and Johnson, Toby and Kapur, Karen and Thorleifsson, Gudmar and Strawbridge, Rona J and Rasmussen-Torvik, Laura J and Esko, T{\~o}nu and Mihailov, Evelin and Fall, Tove and Fraser, Ross M and Mahajan, Anubha and Kanoni, Stavroula and Giedraitis, Vilmantas and Kleber, Marcus E and Silbernagel, G{\"u}nther and Meyer, Julia and M{\"u}ller-Nurasyid, Martina and Ganna, Andrea and Sarin, Antti-Pekka and Yengo, Loic and Shungin, Dmitry and Luan, Jian{\textquoteright}an and Horikoshi, Momoko and An, Ping and Sanna, Serena and Boettcher, Yvonne and Rayner, N William and Nolte, Ilja M and Zemunik, Tatijana and van Iperen, Erik and Kovacs, Peter and Hastie, Nicholas D and Wild, Sarah H and McLachlan, Stela and Campbell, Susan and Polasek, Ozren and Carlson, Olga and Egan, Josephine and Kiess, Wieland and Willemsen, Gonneke and Kuusisto, Johanna and Laakso, Markku and Dimitriou, Maria and Hicks, Andrew A and Rauramaa, Rainer and Bandinelli, Stefania and Thorand, Barbara and Liu, Yongmei and Miljkovic, Iva and Lind, Lars and Doney, Alex and Perola, Markus and Hingorani, Aroon and Kivimaki, Mika and Kumari, Meena and Bennett, Amanda J and Groves, Christopher J and Herder, Christian and Koistinen, Heikki A and Kinnunen, Leena and Faire, Ulf de and Bakker, Stephan J L and Uusitupa, Matti and Palmer, Colin N A and Jukema, J Wouter and Sattar, Naveed and Pouta, Anneli and Snieder, Harold and Boerwinkle, Eric and Pankow, James S and Magnusson, Patrik K and Krus, Ulrika and Scapoli, Chiara and de Geus, Eco J C N and Bl{\"u}her, Matthias and Wolffenbuttel, Bruce H R and Province, Michael A and Abecasis, Goncalo R and Meigs, James B and Hovingh, G Kees and Lindstr{\"o}m, Jaana and Wilson, James F and Wright, Alan F and Dedoussis, George V and Bornstein, Stefan R and Schwarz, Peter E H and T{\"o}njes, Anke and Winkelmann, Bernhard R and Boehm, Bernhard O and M{\"a}rz, Winfried and Metspalu, Andres and Price, Jackie F and Deloukas, Panos and K{\"o}rner, Antje and Lakka, Timo A and Keinanen-Kiukaanniemi, Sirkka M and Saaristo, Timo E and Bergman, Richard N and Tuomilehto, Jaakko and Wareham, Nicholas J and Langenberg, Claudia and M{\"a}nnist{\"o}, Satu and Franks, Paul W and Hayward, Caroline and Vitart, Veronique and Kaprio, Jaakko and Visvikis-Siest, Sophie and Balkau, Beverley and Altshuler, David and Rudan, Igor and Stumvoll, Michael and Campbell, Harry and van Duijn, Cornelia M and Gieger, Christian and Illig, Thomas and Ferrucci, Luigi and Pedersen, Nancy L and Pramstaller, Peter P and Boehnke, Michael and Frayling, Timothy M and Shuldiner, Alan R and Peyser, Patricia A and Kardia, Sharon L R and Palmer, Lyle J and Penninx, Brenda W and Meneton, Pierre and Harris, Tamara B and Navis, Gerjan and Harst, Pim van der and Smith, George Davey and Forouhi, Nita G and Loos, Ruth J F and Salomaa, Veikko and Soranzo, Nicole and Boomsma, Dorret I and Groop, Leif and Tuomi, Tiinamaija and Hofman, Albert and Munroe, Patricia B and Gudnason, Vilmundur and Siscovick, David S and Watkins, Hugh and Lecoeur, Cecile and Vollenweider, Peter and Franco-Cereceda, Anders and Eriksson, Per and Jarvelin, Marjo-Riitta and Stefansson, Kari and Hamsten, Anders and Nicholson, George and Karpe, Fredrik and Dermitzakis, Emmanouil T and Lindgren, Cecilia M and McCarthy, Mark I and Froguel, Philippe and Kaakinen, Marika A and Lyssenko, Valeriya and Watanabe, Richard M and Ingelsson, Erik and Florez, Jose C and Dupuis, Jos{\'e}e and Barroso, In{\^e}s and Morris, Andrew P and Prokopenko, Inga and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)} } @article {475, title = {The trans-ancestral genomic architecture of glycemic traits}, journal = {Nature Genetics}, year = {2021}, month = {05/2021}, pages = {840{\textendash}860}, abstract = {

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30\% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242\ loci (99 novel; P\ \<\ 5\ \×\ 10\−8), 80\% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99\% credible sets by a median of 37.5\%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

}, doi = {10.1038/s41588-021-00852-9}, author = {Chen, Ji and Spracklen, Cassandra N and Marenne, Ga{\"e}lle and Varshney, Arushi and Corbin, Laura J and Luan, Jian{\textquoteright}an and Willems, Sara M and Wu, Ying and Zhang, Xiaoshuai and Horikoshi, Momoko and Boutin, Thibaud S and M{\"a}gi, Reedik and Waage, Johannes and +100Authors} } @article {474, title = {The genetic architecture of the human cerebral cortex}, journal = {Science}, volume = {367}, year = {2020}, pages = {eaay6690}, abstract = {

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 237 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson\’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

}, doi = {10.1126/science.aay6690}, url = {https://www.science.org/doi/abs/10.1126/science.aay6690}, author = {Katrina L. Grasby and Neda Jahanshad and Jodie N. Painter and Luc{\'\i}a Colodro-Conde and Janita Bralten and Derrek P. Hibar and Penelope A. Lind and Fabrizio Pizzagalli and Christopher R. K. Ching and +357Authors} } @article {422, title = {Harmonizing behavioral outcomes across studies, raters, and countries: application to the genetic analysis of aggression in the ACTION Consortium}, journal = {Journal of Child Psychology and Psychiatry}, volume = {61}, year = {2020}, pages = {807{\textendash}817}, abstract = {

BACKGROUND: Aggression in children has genetic and environmental causes. Studies of aggression can pool existing datasets to include more complex models of social effects. Such analyses require large datasets with harmonized outcome measures. Here, we made use of a reference panel for phenotype data to harmonize multiple aggression measures in school-aged children to jointly analyze data from five large twin cohorts.

METHODS: Individual level aggression data on 86,559 children (42,468 twin pairs) were available in five European twin cohorts measured by different instruments. A phenotypic reference panel was collected which enabled a model-based phenotype harmonization approach. A bi-factor integration model in the integrative data analysis framework was developed to model aggression across studies while adjusting for rater, age, and sex. Finally, harmonized aggression scores were analyzed to estimate contributions of genes, environment, and social interaction to aggression. The large sample size allowed adequate power to test for sibling interaction effects, with unique dynamics permitted for opposite-sex twins.

RESULTS: The best-fitting model found a high level of overall heritability of aggression (\ 60\%). Different heritability rates of aggression across sex were marginally significant, with heritability estimates in boys of \ 64\% and \ 58\% in girls. Sibling interaction effects were only significant in the opposite-sex twin pairs: the interaction effect of males on their female co-twin differed from the effect of females on their male co-twin. An aggressive female had a positive effect on male co-twin aggression, whereas more aggression in males had a negative influence on a female co-twin.

CONCLUSIONS: Opposite-sex twins displayed unique social dynamics of aggressive behaviors in a joint analysis of a large, multinational dataset. The integrative data analysis framework, applied in combination with a reference panel, has the potential to elucidate broad, generalizable results in the investigation of common psychological traits in children.

}, keywords = {Aggression, developmental psychopathology, integrative data analysis, phenotype reference panel, twin modeling}, doi = {10.1111/jcpp.13188}, author = {Luningham, Justin M and Hendriks, Anne M and Krapohl, Eva and Fung Ip, Hill and van Beijsterveldt, Catharina E M and Lundstr{\"o}m, Sebastian and Vuoksimaa, Eero and Korhonen, Tellervo and Lichtenstein, Paul and Plomin, Robert and Pulkkinen, Lea and Rose, Richard J and Kaprio, Jaakko and Bartels, Meike and Boomsma, Dorret I and Lubke, Gitta H} } @article {423, title = {Identification, heritability, and relation with gene expression of novel DNA methylation loci for blood pressure}, journal = {Hypertension}, volume = {76}, year = {2020}, pages = {195{\textendash}205}, abstract = {

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P\<1$\times$10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P\<1$\times$10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P\<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61\% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84\% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100\% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.

}, keywords = {blood pressure, DNA methylation, epigenome, hypertension, twin study}, doi = {10.1161/HYPERTENSIONAHA.120.14973}, author = {Huang, Yisong and Ollikainen, Miina and Muniandy, Maheswary and Zhang, Tao and van Dongen, Jenny and Hao, Guang and van der Most, Peter J and Pan, Yue and Pervjakova, Natalia and Sun, Yan V and Hui, Qin and Lahti, Jari and Fraszczyk, Eliza and Lu, Xueling and Sun, Dianjianyi and Richard, Melissa A and Willemsen, Gonneke and Heikkil{\"a}, Kauko and Mateo Leach, Irene and Mononen, Nina and K{\"a}h{\"o}nen, Mika and Hurme, Mikko A and Raitakari, Olli T and Drake, Amanda J and Perola, Markus and Nuotio, Marja-Liisa and Huang, Yunfeng and Khulan, Batbayar and R{\"a}ikk{\"o}nen, Katri and Wolffenbuttel, Bruce H R and Zhernakova, Alexandra and Fu, Jingyuan and Zhu, Haidong and Dong, Yanbin and van Vliet-Ostaptchouk, Jana V and Franke, Lude and Eriksson, Johan G and Fornage, Myriam and Milani, Lili and Lehtim{\"a}ki, Terho and Vaccarino, Viola and Boomsma, Dorret I and van der Harst, Pim and de Geus, Eco J C and Salomaa, Veikko and Li, Shengxu and Chen, Wei and Su, Shaoyong and Wilson, James and Snieder, Harold and Kaprio, Jaakko and Wang, Xiaoling} } @article {407, title = {Anxiety at age 15 predicts psychiatric diagnoses and suicidal ideation in late adolescence and young adulthood: results from two longitudinal studies}, journal = {BMC Psychiatry}, volume = {19}, year = {2019}, pages = {363}, abstract = {

BACKGROUND: Anxiety disorders in adolescence have been associated with several psychiatric outcomes. We sought to describe the prospective relationship between various levels of adolescent anxiety and psychiatric diagnoses (anxiety-, bipolar/psychotic-, depressive-, and alcohol and drug misuse disorders) and suicidal ideation in early adulthood while adjusting for childhood attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental coordination disorder (DCD). Furthermore, we aimed to estimate the proportion attributable to the various anxiety levels for the outcomes.

METHODS: We used a nation-wide population-based Swedish twin study comprising 14,106 fifteen-year-old twins born in Sweden between 1994 and 2002 and a replication sample consisting of 9211 Dutch twins, born between 1985 and 1999. Adolescent anxiety was measured with parental and self-report. Psychiatric diagnoses and suicidal ideation were retrieved from the Swedish National Patient Register and via self-report.

RESULTS: Adolescent anxiety, of various levels, predicted, in the Swedish National Patient Register, anxiety disorders: hazard ratio (HR) = 4.92 (CI 3.33-7.28); depressive disorders: HR = 4.79 (3.23-7.08), and any psychiatric outcome: HR = 3.40 (2.58-4.48), when adjusting for ADHD, ASD, and DCD. The results were replicated in the Dutch data. The proportion of psychiatric outcome attributable to adolescent anxiety over time (age 15-21) was 29\% for any psychiatric outcome, 43-40\% for anxiety disorders, and 39-38\% for depressive disorders.

CONCLUSION: Anxiety in adolescence constitutes an important risk factor in the development of psychiatric outcomes, revealing unique predictions for the different levels of anxiety, and beyond the risk conferred by childhood ADHD, ASD, and DCD. Developmental trajectories leading into psychiatric outcomes should further empirically investigated.

}, keywords = {Adolescence, Anxiety disorders, Depressive disorders, Neurodevelopmental disorders, Suicidal ideation, Young adulthood}, doi = {10.1186/s12888-019-2349-3}, author = {Doering, Sabrina and Lichtenstein, Paul and Gillberg, Christopher and NTR and Middeldorp, Christel M and Bartels, Meike and Kuja-Halkola, Ralf and Lundstr{\"o}m, Sebastian} } @article {292, title = {Assessing Psychopathic Traits Among Children: The First Validation Study of the Child Problematic Traits Inventory in a Clinical Sample}, journal = {Assessment}, year = {2019}, pages = {1073191119832654}, abstract = {

This is the first study that tested the psychometric properties of the Child Problematic Traits Inventory (CPTI) in clinic-referred children (ages 6-13 years). Teachers (N = 159) and parents (N = 173) completed the CPTI and various other measures. Confirmatory factor analyses supported the CPTI\’s three-factor structure when teachers and parents rated the 28 CPTI items. Teacher- and parent-reported CPTI scores showed the expected relations with external correlates (e.g., conduct problems and proactive aggression). Crucially, the validity of the CPTI scores was also supported across informants (i.e., when linking teacher-reported CPTI scores to parent-reported external correlates, and vice versa) and across methods (i.e., regardless if a questionnaire or a diagnostic interview was used to measure external correlates). We conclude that the CPTI holds promise as a research tool for assessing psychopathic traits in clinic-referred children. Until our findings have been replicated and extended, the CPTI should not be used for clinical decision making.

}, doi = {10.1177/1073191119832654}, url = {https://doi.org/10.1177/1073191119832654}, author = {Olivier F. Colins and Peter J. Roetman and Laura Lopez-Romero and Henrik Andershed} } @article {289, title = {Awareness and perceptions of clinical guidelines for the diagnostics and treatment of severe behavioural problems in children across Europe: A qualitative survey with academic experts}, journal = {European PsychiatryEuropean Psychiatry}, volume = {57}, year = {2019}, month = {2019/04/01}, pages = {1 - 9}, abstract = {

Background
Severe behavioural problems (SBPs1) in childhood are highly prevalent, impair functioning, and predict negative outcomes later in life. Over the last decade, clinical practice guidelines for SBPs have been developed across Europe to facilitate the translation of scientific evidence into clinical practice. This study outlines the results of an investigation into academic experts\’ perspectives on the current prevalence, implementation, and utility of clinical guidelines for SBPs in children aged 6\–12 across Europe.

Methods
An online semi-structured questionnaire was completed by 28 psychiatry and psychology experts from 23 countries.

Results
Experts indicated that approximately two thirds of the included European countries use at least an unofficial clinical document such as textbooks, while nearly half possess official guidelines for SBPs. Experts believed that, although useful for practice, guidelines\’ benefits would be maximised if they included more specific recommendations and were implemented more conscientiously. Similarly, experts suggested that unofficial clinical documents offer a wide range of treatment options to individualise treatment from. However, they stressed the need for more consistent, evidence-based clinical practices, by means of developing national and European clinical guidelines for SBPs.

Conclusions
This study offers a preliminary insight into the current successes and challenges perceived by experts around Europe associated with guidelines and documents for SBPs, acting as a stepping stone for future systematic, in-depth investigations of guidelines. Additionally, it establishes experts\’ consensus for the need to develop official guidelines better tailored to clinical practice, creating a momentum for a transition towards European clinical guidelines for this population.

}, isbn = {0924-9338}, url = {https://doi.org/10.1016/j.eurpsy.2018.12.009}, author = {Gatej, Alexandra-Raluca and Lamers, Audri and van Domburgh, Lieke and Crone, Matty and Ogden, Terje and Rijo, Daniel and Aronen, Eeva and Barroso, Ricardo and Boomsma, Dorret I. and Vermeiren, Robert} } @article {294, title = {Children With Early-Onset Disruptive Behavior: Parental Mental Disorders Predict Poor Psychosocial Functioning in Adolescence}, journal = {Journal of the American Academy of Child \& Adolescent Psychiatry}, year = {2019}, abstract = {

Objective
Parental mental disorders (MD) and child early-onset disruptive behavior (DB) are well-established risk factors for poor outcomes in adolescence. However, it is not clear whether parental MD increases risk of future maladjustment among children who already display DB.

Method
Parents of 9-year-old children reported on child DB, while a patient registry was used to determine parental MD. At follow-ups at 15 (N = 6319) and 18 years (N = 3068) information about various problems were collected via registries, parent- and, self-reports.

Results
In the total sample, child DB was related to all outcomes (mean odds ratio [OR] = 1.18; range = 1.07-1.51; ps \< .01), paternal MD to criminality, aggression, truancy, poor school performance, and a cumulative risk index of poor functioning, and maternal MD to peer problems, rule-breaking, and truancy (mean OR = 1.67; range = 1.19-2.71; ps \< .05). In the subsample of children with DB, paternal MD predicted criminality, consequences of antisocial behavior, truancy, poor school performance, and cumulative risk, while maternal MD predicted peer problems (mean OR = 1.94; range = 1.30-2.40; ps \< .05).

Conclusion
This study provides novel evidence that parental MD puts 9-year-olds with DB at risk for negative outcomes in adolescence. Additionally, paternal MD is a better predictor than maternal MD, regardless of child DB at age 9, suggesting that fathers should be given increased attention in future research. Treatment-as-usual of children with DB could be augmented with additional screening and, if necessary, treatment of mental health problems in their parents.

}, isbn = {0890-8567}, url = {https://doi.org/10.1016/j.jaac.2018.10.017}, author = {Roetman, Peter Josse and Lundstr{\"o}m, Sebastian and Finkenauer, Catrin and Vermeiren, Robert Rafa{\"e}l Joseph Marie and Lichtenstein, Paul and Colins, Olivier Frederiek} } @article {290, title = {The Complex Role of Parental Separation in the Association between Family Conflict and Child Problem Behavior}, journal = {Journal of Clinical Child \& Adolescent Psychology}, year = {2019}, pages = {1-15}, abstract = {

Parental separation is a major adverse childhood experience. Parental separation is generally preceded by conflict, which is itself a risk factor for child problem behavior. Whether parental separation independent of conflict has negative effects on child problem behavior is unclear. This study was embedded in Generation R, a population-based cohort followed from fetal life until age 9\ years. Information on family conflict was obtained from 5,808 mothers and fathers. The 4-way decomposition method was used to apportion the effects of prenatal family conflict and parental separation on child problem behavior into 4 nonoverlapping components. Structural equation modeling was used to test bidirectional effects of child problem behavior and family conflict over time. Family conflict from pregnancy onward and parental separation each strongly predicted child problem behavior up to preadolescence according to maternal and paternal ratings. Using the 4-way decomposition method, we found evidence for a strong direct effect of prenatal family conflict on child problem behavior, for reference interaction, and for mediated interaction. The evidence for interaction implies that prenatal family conflict increased the children\’s vulnerability to the harmful effect of parental separation. There was no evidence of a pure indirect effect of parental separation on child problem behavior. Overall, results indicated that if parental separation occurs in families with low levels of conflict, parental separation does not predict more child problem behavior. Moreover, the bidirectional pattern suggested that child problem behavior influences the persistence of family conflict.

}, doi = {10.1080/15374416.2018.1520118}, url = {https://doi.org/10.1080/15374416.2018.1520118}, author = {Yllza Xerxa and Leslie A. Rescorla and Fadila Serdarevic and Marinus H. Van IJzendorn and Vincent W. Jaddoe and Frank C. Verhulst and Maartje P.C.M. Luijk and Henning Tiemeier} } @article {415, title = {Data integration methods for phenotype harmonization in multi-cohort genome-wide association studies with behavioral outcomes}, journal = {Frontiers in Genetics}, volume = {10}, year = {2019}, pages = {1227}, abstract = {

Parallel meta-analysis is a popular approach for increasing the power to detect genetic effects in genome-wide association studies across multiple cohorts. Consortia studying the genetics of behavioral phenotypes are oftentimes faced with systematic differences in phenotype measurement across cohorts, introducing heterogeneity into the meta-analysis and reducing statistical power. This study investigated integrative data analysis (IDA) as an approach for jointly modeling the phenotype across multiple datasets. We put forth a bi-factor integration model (BFIM) that provides a single common phenotype score and accounts for sources of study-specific variability in the phenotype. In order to capitalize on this modeling strategy, a phenotype reference panel was utilized as a supplemental sample with complete data on all behavioral measures. A simulation study showed that a mega-analysis of genetic variant effects in a BFIM were more powerful than meta-analysis of genetic effects on a cohort-specific sum score of items. Saving the factor scores from the BFIM and using those as the outcome in meta-analysis was also more powerful than the sum score in most simulation conditions, but a small degree of bias was introduced by this approach. The reference panel was necessary to realize these power gains. An empirical demonstration used the BFIM to harmonize aggression scores in 9-year old children across the Netherlands Twin Register and the Child and Adolescent Twin Study in Sweden, providing a template for application of the BFIM to a range of different phenotypes. A supplemental data collection in the Netherlands Twin Register served as a reference panel for phenotype modeling across both cohorts. Our results indicate that model-based harmonization for the study of complex traits is a useful step within genetic consortia.

}, keywords = {consortia, data integration, genome-wide association studies, latent variable modeling, phenotype harmonization}, doi = {10.3389/fgene.2019.01227}, author = {Luningham, Justin M and McArtor, Daniel B and Hendriks, Anne M and van Beijsterveldt, Catharina E M and Lichtenstein, Paul and Lundstr{\"o}m, Sebastian and Larsson, Henrik and Bartels, Meike and Boomsma, Dorret I and Lubke, Gitta H} } @article {419, title = {The heritability of self-control: A meta-analysis}, journal = {Neuroscience \& Biobehavioral Reviews}, volume = {100}, year = {2019}, pages = {324{\textendash}334}, abstract = {

Self-control is the ability to control one\&$\#$39;s impulses when faced with challenges or temptations, and is robustly associated with physiological and psychological well-being. Twin studies show that self-control is heritable, but estimates range between 0\% and 90\%, making it difficult to draw firm conclusions. The aim of this study was to perform a meta-analysis to provide a quantitative overview of the heritability of self-control. A systematic search resulted in 31 included studies, 17 reporting on individual samples, based on a sample size of \>30,000 twins, published between 1997 and 2018. Our results revealed an overall monozygotic twin correlation of 0.58, and an overall dizygotic twin correlation of 0.28, resulting in a heritability estimate of 60\%. The heritability of self-control did not vary across gender or age. The heritability did differ across informants, with stronger heritability estimates based on parent report versus self-report or observations. This finding provides evidence that when aiming to understand individual differences in self-control, one should take genetic factors into account. Recommendations for future research are discussed.

}, keywords = {genetics, heritability, meta-analysis, self-control, Twin}, doi = {10.1016/j.neubiorev.2019.02.012}, author = {Willems, Y E and Boesen, N and Li, J and Finkenauer, C and Bartels, M} } @article {409, title = {Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight}, journal = {Nature Communications}, volume = {10}, year = {2019}, pages = {1893}, abstract = {

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from \−183 to 178 grams per 10\% increase in methylation (PBonferroni\ \<\ 1.06\ x\ 10\−7). In additional analyses in 7,278 participants, \<1.3\% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood.\ Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p\ = 6.12\ x\ 10\−74) and BMI in pregnancy (3/914, p = 1.13x10\−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

}, doi = {10.1038/s41467-019-09671-3}, author = {K{\"u}pers, Leanne K and Monnereau, Claire and Sharp, Gemma C and Yousefi, Paul and Salas, Lucas A and Ghantous, Akram and Page, Christian M and Reese, Sarah E and Wilcox, Allen J and Czamara, Darina and Starling, Anne P and Novoloaca, Alexei and Lent, Samantha and Roy, Ritu and Hoyo, Cathrine and Breton, Carrie V and Allard, Catherine and Just, Allan C and Bakulski, Kelly M and Holloway, John W and Everson, Todd M and Xu, Cheng-Jian and Huang, Rae-Chi and van der Plaat, Diana A and Wielscher, Matthias and Merid, Simon Kebede and Ullemar, Vilhelmina and Rezwan, Faisal I and Lahti, Jari and van Dongen, Jenny and Langie, Sabine A S and Richardson, Tom G and Magnus, Maria C and Nohr, Ellen A and Xu, Zongli and Duijts, Liesbeth and Zhao, Shanshan and Zhang, Weiming and Plusquin, Michelle and DeMeo, Dawn L and Solomon, Olivia and Heimovaara, Joosje H and Jima, Dereje D and Gao, Lu and Bustamante, Mariona and Perron, Patrice and Wright, Robert O and Hertz-Picciotto, Irva and Zhang, Hongmei and Karagas, Margaret R and Gehring, Ulrike and Marsit, Carmen J and Beilin, Lawrence J and Vonk, Judith M and Jarvelin, Marjo-Riitta and Bergstr{\"o}m, Anna and {\"O}rtqvist, Anne K and Ewart, Susan and Villa, Pia M and Moore, Sophie E and Willemsen, Gonneke and Standaert, Arnout R L and H\aaberg, Siri E and S{\o}rensen, Thorkild I A and Taylor, Jack A and R{\"a}ikk{\"o}nen, Katri and Yang, Ivana V and Kechris, Katerina and Nawrot, Tim S and Silver, Matt J and Gong, Yun Yun and Richiardi, Lorenzo and Kogevinas, Manolis and Litonjua, Augusto A and Eskenazi, Brenda and Huen, Karen and Mbarek, Hamdi and Maguire, Rachel L and Dwyer, Terence and Vrijheid, Martine and Bouchard, Luigi and Baccarelli, Andrea A and Croen, Lisa A and Karmaus, Wilfried and Anderson, Denise and de Vries, Maaike and Sebert, Sylvain and Kere, Juha and Karlsson, Robert and Arshad, Syed Hasan and H{\"a}m{\"a}l{\"a}inen, Esa and Routledge, Michael N and Boomsma, Dorret I and Feinberg, Andrew P and Newschaffer, Craig J and Govarts, Eva and Moisse, Matthieu and Fallin, M Daniele and Mel{\'e}n, Erik and Prentice, Andrew M and Kajantie, Eero and Almqvist, Catarina and Oken, Emily and Dabelea, Dana and Boezen, H Marike and Melton, Phillip E and Wright, Rosalind J and Koppelman, Gerard H and Trevisi, Letizia and Hivert, Marie-France and Sunyer, Jordi and Munthe-Kaas, Monica C and Murphy, Susan K and Corpeleijn, Eva and Wiemels, Joseph and Holland, Nina and Herceg, Zdenko and Binder, Elisabeth B and Davey Smith, George and Jaddoe, Vincent W V and Lie, Rolv T and Nystad, Wenche and London, Stephanie J and Lawlor, Debbie A and Relton, Caroline L and Snieder, Harold and Felix, Janine F} } @article {414, title = {The Netherlands Twin Register: Longitudinal research based on twin and twin-family designs}, journal = {Twin Research and Human Genetics}, volume = {22}, year = {2019}, pages = {623{\textendash}636}, abstract = {

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.

}, keywords = {biobank, endophenotyping, longitudinal phenotyping, multigeneration pedigree, twins, zygosity}, doi = {10.1017/thg.2019.93}, author = {Ligthart, Lannie and van Beijsterveldt, Catharina E M and Kevenaar, Sofieke T and de Zeeuw, Eveline and van Bergen, Elsje and Bruins, Susanne and Pool, Ren{\'e} and Helmer, Quinta and van Dongen, Jenny and Hottenga, Jouke-Jan and Van{\textquoteright}t Ent, Dennis and Dolan, Conor V and Davies, Gareth E and Ehli, Erik A and Bartels, Meike and Willemsen, Gonneke and de Geus, Eco J C and Boomsma, Dorret I} } @article {408, title = {Testing bidirectional associations between childhood aggression and BMI: Results from three cohorts}, journal = {Obesity (Silver Spring)}, volume = {27}, year = {2019}, pages = {822{\textendash}829}, abstract = {

OBJECTIVE: This study examined the prospective, potentially bidirectional association of aggressive behavior with BMI and body composition across childhood in three population-based cohorts.

METHODS: Repeated measures of aggression and BMI were available from the Generation R Study between ages 6 and 10 years (N = 3,974), the Netherlands Twin Register (NTR) between ages 7 and 10 years (N = 10,328), and the Swedish Twin Study of Child and Adolescent Development (TCHAD) between ages 9 and 14 years (N = 1,462). In all samples, aggression was assessed with the Child Behavior Checklist. Fat mass and fat-free mass were available in the Generation R Study. Associations were examined with cross-lagged modeling.

RESULTS: Aggressive behavior at baseline was associated with higher BMI at follow-up in the Generation R Study ($\beta$ = 0.02, 95\% CI: 0.00 to 0.04), in NTR ($\beta$ = 0.04, 95\% CI: 0.02 to 0.06), and in TCHAD ($\beta$ = 0.03, 95\% CI: -0.02 to 0.07). Aggressive behavior was prospectively associated with higher fat mass ($\beta$ = 0.03, 95\% CI: 0.01 to 0.05) but not fat-free mass. There was no evidence that BMI or body composition preceded aggressive behavior.

CONCLUSIONS: More aggressive behavior was prospectively associated with higher BMI and fat mass. This suggests that aggression contributes to the obesity problem, and future research should study whether these behavioral pathways to childhood obesity are modifiable.

}, doi = {10.1002/oby.22419}, author = {Derks, Ivonne P M and Bolhuis, Koen and Yalcin, Zeynep and Gaillard, Romy and Hillegers, Manon H J and Larsson, Henrik and Lundstr{\"o}m, Sebastian and Lichtenstein, Paul and van Beijsterveldt, Catharina E M and Bartels, Meike and Boomsma, Dorret I and Tiemeier, Henning and Jansen, Pauline W} } @article {236, title = {Adult aggressive behavior in humans and biomarkers: a focus on lipids and methylation}, journal = {Journal of Pediatric and Neonatal Individualized Medicine (JPNIM)}, volume = {7}, year = {2018}, month = {04/2018}, abstract = {

Aggression shows large variation between individuals, with about 50\% explained by genetic factors. Biomarkers related to aggression have been reported for lipid metabolism and for epigenetic marks. Methylation and blood lipid levels are not independent and differential methylation can be a consequence of variation in blood lipid levels. We hypothesized that the methylation level of such loci in blood can inform us if aggression is associated with long-term exposure to lipid levels. If this is the case, we expect to find that loci where methylation levels are influenced by lipid levels to show differential methylation in aggressive individuals. Such loci might complement classic lipid level measures as a biomarker for lipid-related disturbances in aggression. As a first step, we examined the association of lipid levels and related biomarkers with aggression in a large adult population cohort (N = 5,588) and in 31 monozygotic (MZ) twin pairs who were discordant for aggression, as well as 12 extremely discordant MZ pairs. Biomarkers were not significantly associated with aggression in the population cohort. In the discordant MZ pairs we identified significant within-pair differences for glucose and marginally significant differences for lipids and cytokines, with the more aggressive twin showing lower levels of glucose and low density lipoprotein cholesterol and higher levels of fibrinogen, C-reactive protein and interleukin-6. The analysis of epigenetic data in the MZ pairs discordant for aggression did not show enrichment for lipid cytosine guanine dinucleotides (CpGs) and we observed no enrichment of lipid CpGs in an epigenome-wide association study of aggression in the population cohort. These results did not support the hypothesis that lipid CpGs show differential methylation in adult aggression. A next step will be to examine the role of biomarkers in aggression across the lifespan, including childhood, and to explore a more holistic biomarker approach, such as offered by metabolomics.

PDF Available here

}, keywords = {adult aggression, biomarkers, discordant twin pairs, epigenetics, lipids}, doi = {10.7363/070204}, url = {http://www.jpnim.com/index.php/jpnim/article/view/070204}, author = {Fiona Hagenbeek and Jenny van Dongen and Kluft, Cornelis and Thomas Hankemeier and Lannie Ligthart and Gonneke Willemsen and de Geus, Eco J.C. and Vink, Jacqueline M. and Meike Bartels and Dorret I. Boomsma} } @article {251, title = {The Associations between Callous-unemotional Traits and Symptoms of Conduct Problems, Hyperactivity and Emotional Problems: A Study of Adolescent Twins Screened for Neurodevelopmental Problems}, journal = {Journal of Abnormal Child Psychology}, year = {2018}, month = {May}, abstract = {

Callous-unemotional (CU) traits (e.g., lack of empathy, lack of guilt, shallow affect) are associated with severe and persistent conduct problems in youth. There is evidence showing a substantial genetic correlation between CU traits and conduct problems. The etiological associations between CU traits and other psychopathological symptoms, including symptoms of hyperactivity and emotional problems (such as anxiety and depression symptoms), have been less explored. To examine the etiological associations between CU traits and symptoms of conduct problems, hyperactivity and emotional problems separately through the use of a twin design. Participants were same-sex twin pairs (n{\th}inspace}={\th}inspace}426 twins; 42{\%} female; 43{\%} MZ; age{\th}inspace}={\th}inspace}15) drawn from the Child and Adolescents Twin Study in Sweden, a longitudinal study of twins born in Sweden. The sample was mainly composed of children who screenpositive on neurodevelopmental problems/mental health problems or at-risk children (i.e., screen-negative children considered to be genetically at-risk siblings). We used self-report measures of CU traits, conduct problems, hyperactivity and emotional problems. Model-fitting analyses were conducted using structural equation modeling. We found a strong positive genetic correlation between CU traits and conduct problems and a moderate genetic correlation between CU traits and hyperactivity. We also found a relatively modest, but significant negative genetic correlation between CU traits and emotional problems. Using a sample of adolescent twins screened for neurodevelopmental problems, we replicated previous findings that showed a strong genetic correlation between CU traits and conduct problems and we extended research by examining further the etiological associations between CU traits and symptoms of hyperactivity and emotional problems.

}, issn = {1573-2835}, doi = {10.1007/s10802-018-0439-1}, url = {https://doi.org/10.1007/s10802-018-0439-1}, author = {Saunders, Marie Claire and Anckars{\"a}ter, Henrik and Lundstr{\"o}m, Sebastian and Hellner, Clara and Lichtenstein, Paul and Fontaine, Nathalie M. G.} } @article {252, title = {Associations Between Conduct Disorder, Neurodevelopmental Problems and Psychopathic Personality Traits in a Swedish Twin Youth Population}, journal = {Journal of Psychopathology and Behavioral Assessment}, volume = {40}, year = {2018}, month = {Dec}, pages = {586{\textendash}592}, abstract = {

Previous research has found a complex relationship between psychopathic traits, neurodevelopmental problems (NDPs), and conduct disorder (CD) in children. This study explores associations between psychopathic traits, assessed with the Child Problematic Traits Inventory\–-Short Version (CPTI-SV), and CD in children with and without coexisting NDPs (i.e., attention deficit/hyperactivity disorder [ADHD] and autism spectrum disorder [ASD]) in a community-based sample of Swedish twins (n{\th}inspace}={\th}inspace}8762). Findings indicate weak to moderately strong correlations between psychopathic traits and CD, ADHD, and ASD, respectively. Furthermore, in univariable analyses, both psychopathic traits and NDPs displayed significant positive associations with being screened positive for CD, though only the grandiose-deceitful dimension of CPTI-SV and the ADHD domain concentration and attention deficits remained significantly associated with CD in a multivariable regression model. The results are relevant to screening and assessment in child and youth psychiatry, as a grandiose and deceitful interpersonal style may also be a valid sign of children at risk of developing CD.

}, issn = {1573-3505}, doi = {10.1007/s10862-018-9689-z}, url = {https://doi.org/10.1007/s10862-018-9689-z}, author = {Svensson, Olof and S{\"o}rman, Karolina and Durbeej, Natalie and Lichtenstein, Paul and Anckars{\"a}ter, Henrik and Kerekes, Nora and Nilsson, Thomas} } @article {230, title = {Childhood aggression and the co-occurrence of behavioural and emotional problems: results across ages 3{\textendash}16~years from multiple raters in six cohorts in the EU-ACTION project}, journal = {European Child {\&} Adolescent Psychiatry}, year = {2018}, month = {May}, abstract = {

Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. We focus on the co-occurrence of aggression and other childhood behavioural and emotional problems, including other externalising problems, attention problems and anxiety\–depression. The data were brought together within the EU-ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies) project. We analysed the co-occurrence of aggression and other childhood behavioural and emotional problems as a function of the child\&$\#$39;s age (ages 3 through 16\ years), gender, the person rating the behaviour (father, mother or self) and assessment instrument. The data came from six large population-based European cohort studies from the Netherlands (2x), the UK, Finland and Sweden (2x). Multiple assessment instruments, including the Child Behaviour Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ) and Multidimensional Peer Nomination Inventory (MPNI), were used. There was a good representation of boys and girls in each age category, with data for 30,523 3- to 4-year-olds (49.5{\%} boys), 20,958 5- to 6-year-olds (49.6{\%} boys), 18,291 7- to 8-year-olds (49.0{\%} boys), 27,218 9- to 10-year-olds (49.4{\%} boys), 18,543 12- to 13-year-olds (48.9{\%} boys) and 10,088 15- to 16-year-olds (46.6{\%} boys). We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender differences decreased with age and were not present for self-reports. Aggression co-occurred with the majority of other behavioural and social problems, from both externalising and internalising domains. At each age, the co-occurrence was particularly prevalent for aggression and oppositional and ADHD-related problems, with correlations of around 0.5 in general. Aggression also showed substantial associations with anxiety\–depression and other internalizing symptoms (correlations around 0.4). Co-occurrence for self-reported problems was somewhat higher than for parental reports, but we found neither rater differences, nor differences across assessment instruments in co-occurrence patterns. There were large similarities in co-occurrence patterns across the different European countries. Finally, co-occurrence was generally stable across age and sex, and if any change was observed, it indicated stronger correlations when children grew older. We present an online tool to visualise these associations as a function of rater, gender, instrument and cohort. In addition, we present a description of the full EU-ACTION projects, its first results and the future perspectives.

Related interactive tool here.

}, issn = {1435-165X}, doi = {10.1007/s00787-018-1169-1}, url = {https://doi.org/10.1007/s00787-018-1169-1}, author = {Meike Bartels and Anne Hendriks and Matteo Mauri and Eva Krapohl and Alyce Whipp and Koen Bolhuis and Conde, Lucia Colodro and Luningham, Justin and Fung Ip, Hill and Fiona Hagenbeek and Roetman, Peter and Gatej, Raluca and Lamers, Audri and Michel G. Nivard and Jenny van Dongen and Lu, Yi and Christel Middeldorp and van Beijsterveldt, Toos and Vermeiren, Robert and Thomas Hankemeier and Kluft, Cees and Medland, Sarah and Lundstr{\"o}m, Sebastian and Richard J. Rose and Pulkkinen, Lea and Vuoksimaa, Eero and Korhonen, Tellervo and Martin, Nicholas G. and Gitta Lubke and Catrin Finkenauer and Vassilios Fanos and Henning Tiemeier and Lichtenstein, Paul and Robert Plomin and Kaprio, Jaakko and Dorret I. Boomsma} } @article {268, title = {Criterion Validity and Utility of the General Factor of Psychopathology in Childhood: Predictive Associations With Independently Measured Severe Adverse Mental Health Outcomes in Adolescence}, journal = {Journal of the American Academy of Child \& Adolescent Psychiatry}, volume = {57}, year = {2018}, pages = {372 - 383}, abstract = {

Objective

We examined whether a parent-rated general factor of psychopathology in childhood would predict independently measured, severe adverse mental health outcomes in adolescence.

Method

We used the Child and Adolescent Twin Study in Sweden, which targets all twin children in Sweden. Parents rated their children (N = 16,806) on 43 symptoms of inattention, hyperactivity/impulsivity, conduct problems, and anxiety/emotionality when the twins turned 9 or 12 years of age. Adverse mental health outcomes in adolescence were retrieved from national registers, and included psychiatric diagnoses, prescription of anxiolytic or antidepressant medication, court convictions of crimes, and failure to achieve eligibility for high school.

Results

Parent-rated inattention, hyperactivity/impulsivity, conduct problems, and anxiety/emotionality in childhood predicted all adverse mental health outcomes in adolescence (mean odds ratio = 1.76; range = 1.41\−2.18; all p \< .05). However, several of these associations were nonsignificant in a multiple regression framework, suggesting the influence of common variance. A general factor of psychopathology uniquely predicted all outcomes (mean odds ratio = 1.58; range = 1.34\−1.84; all p \< .05), whereas the specific factors predicted only a subset of the outcomes.

Conclusion

Mental health problems in childhood are associated with a host of adverse outcomes in adolescence, and, to a considerable extent, these associations are driven by a general factor of psychopathology. The general factor may therefore be important to clinical prognosis, which informs clinical decision making for children.

}, keywords = {-factor, bifactor, General factor of psychopathology, heterotypic continuity}, issn = {0890-8567}, doi = {https://doi.org/10.1016/j.jaac.2017.12.016}, url = {http://www.sciencedirect.com/science/article/pii/S0890856718301667}, author = {Erik Pettersson and Benjamin B Lahey and Henrik Larsson and Paul Lichtenstein} } @article {261, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis}, journal = {Blood}, year = {2018}, abstract = {

Elevated epigenetic age is associated with an altered hemostatic factor profile and lower clotting time (aPTT).DNA methylation age is associated with mRNA levels of fibrinogen in multiple tissues. Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {0006-4971}, doi = {10.1182/blood-2018-02-831347}, url = {http://www.bloodjournal.org/content/early/2018/07/24/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K. and Huffman, Jennifer E. and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W. David and Jhun, Min A. and Brody, Jennifer A. and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S. and de Vries, Paul S. and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J. and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S. and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C. and Boerwinkle, Eric and Wiggins, Kerri L. and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M. and Sotoodenia, Nona and Dorret I. Boomsma and Gonneke Willemsen and Lannie Ligthart and Deary, Ian J. and Zhao, Wei and Ware, Erin B. and Kardia, Sharon L.R. and Joyce B.J. Van Meurs and Uitterlinden, Andre G. and Franco, Oscar H. and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S. and Johnson, Andrew D. and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J.C. and Starr, John M. and Smith, Jennifer A. and Dehghan, Abbas and Bj{\"o}rck, Hanna M. and Smith, Nicholas L. and Peters, Annette} } @article {277, title = {During day and night: Childhood psychotic experiences and objective and subjective sleep problems}, journal = {Schizophrenia Research}, year = {2018}, abstract = {

Background
Psychotic experiences comprise auditory and visual perceptive phenomena, such as hearing or seeing things that are not there, in the absence of a psychotic disorder. Psychotic experiences commonly occur in the general pediatric population. Although the majority of psychotic experiences are transient, they are predictive of future psychotic and non-psychotic disorders. They have been associated with sleep problems, but studies with objective sleep measures are lacking. This study assessed whether psychotic experiences were associated with actigraphic sleep measures, symptoms of dyssomnia, nightmares, or other parasomnias.


Methods
This cross-sectional population-based study comprises 4149 children from the Generation R Study. At age 10 years, psychotic experiences including hallucinatory phenomena were assessed by self-report; dyssomnia and parasomnia symptoms were assessed by mother- and child-report. Additionally, at age 11 years, objective sleep parameters were measured using a tri-axial wrist accelerometer in N = 814 children, who wore the accelerometer for five consecutive school days.

Results
Psychotic experiences were not associated with objective sleep duration, sleep efficiency, arousal, or social jetlag. However, psychotic experiences were associated with self-reported dyssomnia (B = 2.45, 95\%CI: 2.13\–2.77, p \< 0.001) and mother-reported parasomnia, specifically nightmares (ORadjusted = 3.59, 95\%CI 2.66\–4.83, p \< 0.001). Similar results were found when analyses were restricted to hallucinatory phenomena.

Conclusions
Childhood psychotic experiences were not associated with objective sleep measures. In contrast, psychotic experiences were associated with nightmares, which are a known risk indicator of psychopathology in pre-adolescence. More research is needed to shed light on the potential etiologic or diagnostic role of nightmares in the development of psychotic phenomena.

}, keywords = {Actigraphy, General population, Hallucinatory phenomena, Parasomnia, Psychosis, Social jetlag}, issn = {0920-9964}, doi = {https://doi.org/10.1016/j.schres.2018.12.002}, url = {http://www.sciencedirect.com/science/article/pii/S0920996418306911}, author = {M. Elisabeth Koopman-Verhoeff and Koen Bolhuis and Charlotte A.M. Cecil and Desana Kocevska and J.J. Hudziak and Manon H.J. Hillegers and Viara R. Mileva-Seitz and Irwin K. Reiss and Liesbeth Duijts and Frank Verhulst and Maartje P.C.M. Luijk and Henning Tiemeier} } @article {272, title = {Environmental sensitivity in children: Development of the Highly Sensitive Child Scale and identification of sensitivity groups.}, journal = {Developmental Psychology}, volume = {54}, year = {2018}, month = {2018}, pages = {51 - 70}, abstract = {

A large number of studies document that children differ in the degree they are shaped by their developmental context with some being more sensitive to environmental influences than others. Multiple theories suggest that Environmental Sensitivity is a common trait predicting the response to negative as well as positive exposures. However, most research to date has relied on more or less proximal markers of Environmental Sensitivity. In this paper we introduce a new questionnaire\—the Highly Sensitive Child (HSC) scale\—as a promising self-report measure of Environmental Sensitivity. After describing the development of the short 12-item HSC scale for children and adolescents, we report on the psychometric properties of the scale, including confirmatory factor analysis and test\–retest reliability. After considering bivariate and multivariate associations with well-established temperament and personality traits, we apply Latent Class Analysis to test for the existence of hypothesized sensitivity groups. Analyses are conducted across 5 studies featuring 4 different U.K.-based samples ranging in age from 8\–19 years and with a total sample size of N = 3,581. Results suggest the 12-item HSC scale is a psychometrically robust measure that performs well in both children and adolescents. Besides being relatively independent from other common traits, the Latent Class Analysis suggests that there are 3 distinct groups with different levels of Environmental Sensitivity\—low (approx. 25\–35\%), medium (approx. 41\–47\%), and high (20\–35\%). Finally, we provide exploratory cut-off scores for the categorization of children into these different groups which may be useful for both researchers and practitioners. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

}, keywords = {*Childhood Development, *Personality Development, *Sensitivity (Personality), Factor Analysis, Rating Scales, Test Construction, Test Reliability}, isbn = {1939-0599(Electronic),0012-1649(Print)}, author = {Pluess, Michael and Assary, Elham and Lionetti, Francesca and Lester, Kathryn J. and Eva Krapohl and Aron, Elaine N. and Aron, Arthur} } @article {271, title = {Evidence for gene-environment correlation in child feeding: Links between common genetic variation for BMI in children and parental feeding practices}, journal = {PLOS Genetics}, volume = {14}, year = {2018}, month = {11}, pages = {1-19}, abstract = {

The parental feeding practices (PFPs) of excessive restriction of food intake (\‘restriction\’) and pressure to increase food consumption (\‘pressure\’) have been argued to causally influence child weight in opposite directions (high restriction causing overweight; high pressure causing underweight). However child weight could also \‘elicit\’ PFPs. A novel approach is to investigate gene-environment correlation between child genetic influences on BMI and PFPs. Genome-wide polygenic scores (GPS) combining BMI-associated variants were created for 10,346 children (including 3,320 DZ twin pairs) from the Twins Early Development Study using results from an independent genome-wide association study meta-analysis. Parental \‘restriction\’ and \‘pressure\’ were assessed using the Child Feeding Questionnaire. Child BMI standard deviation scores (BMI-SDS) were calculated from children\’s height and weight at age 10. Linear regression and fixed family effect models were used to test between- (n = 4,445 individuals) and within-family (n = 2,164 DZ pairs) associations between the GPS and PFPs. In addition, we performed multivariate twin analyses (n = 4,375 twin pairs) to estimate the heritabilities of PFPs and the genetic correlations between BMI-SDS and PFPs. The GPS was correlated with BMI-SDS (β = 0.20, p = 2.41x10-38). Consistent with the gene-environment correlation hypothesis, child BMI GPS was positively associated with \‘restriction\’ (β = 0.05, p = 4.19x10-4), and negatively associated with \‘pressure\’ (β = -0.08, p = 2.70x10-7). These results remained consistent after controlling for parental BMI, and after controlling for overall family contributions (within-family analyses). Heritabilities for \‘restriction\’ (43\% [40\–47\%]) and \‘pressure\’ (54\% [50\–59\%]) were moderate-to-high. Twin-based genetic correlations were moderate and positive between BMI-SDS and \‘restriction\’ (rA = 0.28 [0.23\–0.32]), and substantial and negative between BMI-SDS and \‘pressure\’ (rA = -0.48 [-0.52 - -0.44]. Results suggest that the degree to which parents limit or encourage children\’s food intake is partly influenced by children\’s genetic predispositions to higher or lower BMI. These findings point to an evocative gene-environment correlation in which heritable characteristics in the child elicit parental feeding behaviour.

}, doi = {10.1371/journal.pgen.1007757}, url = {https://doi.org/10.1371/journal.pgen.1007757}, author = {Saskia Selzam and McAdams, Tom A. and Jonathan R I Coleman and Carnell, Susan and Paul F O{\textquoteright}Reilly and Robert Plomin and Llewellyn, Clare H.} } @article {228, title = {Genetic and environmental contributions to the development of childhood aggression.}, journal = {Developmental psychology}, volume = {54 1}, year = {2018}, pages = {39-50}, abstract = {

Longitudinal data from a large sample of twins participating in the Netherlands Twin Register (n = 42,827, age range 3-16) were analyzed to investigate the genetic and environmental contributions to childhood aggression. Genetic auto-regressive (simplex) models were used to assess whether the same genes are involved or whether new genes come into play as children grow up. The authors compared 2 different simplex models to disentangle potentially changing behavioral expressions from changes in genetic and environmental effects. One model provided estimates of genetic and environmental effects at the level of individual aggression questionnaire items, and the other model assessed the effects at the level of an aggression sum score computed from the individual items. The results from both models provided evidence for largely stable genetic effects throughout childhood. The results also highlighted the differential heritability of the different indicators of aggression measured with the Childhood Behavior Checklist, with destruction of property showing a very high genetic component during early childhood and fighting behaviors being more heritable in early adolescence. (PsycINFO Database Record.

}, author = {Gitta Lubke and Daniel B. McArtor and Dorret I. Boomsma and Meike Bartels} } @article {404, title = {A genome-wide association study for extremely high intelligence}, journal = {Molecular Psychiatry}, volume = {23}, year = {2018}, pages = {1226{\textendash}1232}, abstract = {

We used a case\–control genome-wide association (GWA) design with cases consisting of 1238 individuals from the top 0.0003 (~170 mean IQ) of the population distribution of intelligence and 8172 unselected population-based controls. The single-nucleotide polymorphism heritability for the extreme IQ trait was 0.33 (0.02), which is the highest so far for a cognitive phenotype, and significant genome-wide genetic correlations of 0.78 were observed with educational attainment and 0.86 with population IQ. Three variants in locus ADAM12 achieved genome-wide significance, although they did not replicate with published GWA analyses of normal-range IQ or educational attainment. A genome-wide polygenic score constructed from the GWA results accounted for 1.6\% of the variance of intelligence in the normal range in an unselected sample of 3414 individuals, which is comparable to the variance explained by GWA studies of intelligence with substantially larger sample sizes. The gene family plexins, members of which are mutated in several monogenic neurodevelopmental disorders, was significantly enriched for associations with high IQ. This study shows the utility of extreme trait selection for genetic study of intelligence and suggests that extremely high intelligence is continuous genetically with normal-range intelligence in the population.

}, doi = {https://doi.org/10.1038/mp.2017.121}, author = {Zabaneh, D and Krapohl, E and Gaspar, H A and Curtis, C and Lee, S H and Patel, H and Newhouse, S and Wu, H M and Simpson, M A and Putallaz, M and Lubinski, D and Plomin, R and Breen, G} } @article {273, title = {Preconception and prenatal cannabis use and the risk of behavioural and emotional problems in the offspring; a multi-informant prospective longitudinal study}, journal = {International Journal of Epidemiology}, year = {2018}, pages = {dyy186}, abstract = {

Background:

Studies of the long-term consequences of maternal cannabis use on child development beyond the neonatal period are sparse. In the current study, we use a multi-information approach to assess the association of prenatal cannabis exposure and child behavioural and emotional functioning. To explore the possible causal nature of the association, we investigated whether maternal tobacco and paternal cannabis use during pregnancy were also associated with child problems.

Methods:

The study population included children of a population-based birth cohort in The Netherlands (n = 5903). Information on parental cannabis use was collected using questionnaires; urine of mothers was analysed for the presence of cannabis metabolites. Child behavioural and emotional problems at approximately 7-10\ years were measured using validated teacher-, child- and mother-reports.

Results:

Our findings show associations of maternal cannabis use during pregnancy with offspring externalising problems (B = 0.53; 95\% CI: 0.29-0.77), but not with internalising problems (B = -0.10; 95\% CI: -0.31-0.11). However, maternal cannabis use before pregnancy was also associated with offspring externalising problems (B = 0.27; 95\% CI: 0.02-0.52). Further, cannabis use by the father was associated with child externalising problems (B = 0.36; 95\% CI: 0.22-0.49) but not internalising problems.

Conclusions:

Prenatal exposure to maternal cannabis use is specifically associated with offspring behavioural problems, but not emotional problems. This association is probably not due to an effect of intrauterine cannabis exposure on fetal development, because both maternal and paternal cannabis exposure during pregnancy were related to offspring externalising problems. Our findings suggest that the association can be explained through residual confounding, most likely through shared genetic vulnerabilities for parental cannabis use and offspring behavioural problems.

}, doi = {10.1093/ije/dyy186}, url = {http://dx.doi.org/10.1093/ije/dyy186}, author = {Hanan El Marroun and Koen Bolhuis and Franken, Ingmar H A and Vincent W.V. Jaddoe and Manon H.J. Hillegers and Benjamin B Lahey and Henning Tiemeier} } @article {247, title = {The relation between the age at diagnosis of problem behaviors related to aggression and distal outcomes in Swedish children}, journal = {European Child {\&} Adolescent Psychiatry}, year = {2018}, month = {Nov}, abstract = {

Severe childhood aggressive behaviors are known to predict negative outcomes later in life; however, little is known about the effect of when in childhood aggression problems are diagnosed. While an earlier first diagnosis of problematic aggressive behavior might be associated with increased severity and, thus, worse outcomes, it is also possible that an earlier diagnosis affords an earlier start of treatment programs or indicates that greater attention is being paid to behavioral problems, thus resulting in attenuation of the severity of childhood aggression\&$\#$39;s impact on distal outcomes. The current study analyzed data from the population-based Swedish Data Registries, which include data on all children formally diagnosed by the Swedish medical system with a wide range of aggression problems between ages 8 and 18 (N{\th}inspace}={\th}inspace}5816) during the years 1987\–2013, along with a matched control. Time-to-event analyses investigated whether the age at time of diagnosis affects later life outcomes while controlling for relevant confounders. Results show that for both boys and girls, those with a later diagnosis had lower average incomes (regression coefficient b{\th}inspace}={\th}inspace}\−{\th}inspace}0.055, p{\th}inspace}\<{\th}inspace}0.005) and a higher probability of having a criminal record (odds ratio 1.126, p{\th}inspace}\<{\th}inspace}0.005) than children with earlier diagnoses. The effect on suicide attempts was not significant after correcting for multiple testing (odds ratio 1.264, p{\th}inspace}={\th}inspace}0.016). Grade score was not significantly affected. The results warrant further research concerning the potential advantage of earlier diagnoses, especially concerning generalizability beyond the Swedish population.

}, issn = {1435-165X}, doi = {10.1007/s00787-018-1250-9}, url = {https://doi.org/10.1007/s00787-018-1250-9}, author = {Ian Campbell and Lundstr{\"o}m, Sebastian and Henrik Larsson and Lichtenstein, Paul and Gitta Lubke} } @article {405, title = {Risk factors for parental psychopathology: a study in families with children or adolescents with psychopathology}, journal = {European Child \& Adolescent Psychiatry}, volume = {27}, year = {2018}, pages = {1575{\textendash}1584}, abstract = {

The parents of children with psychopathology are at increased risk for psychiatric symptoms. To investigate which parents are mostly at risk, we assessed in a clinical sample of families with children with psychopathology, whether parental symptom scores can be predicted by offspring psychiatric diagnoses and other child, parent and family characteristics. Parental depressive, anxiety, avoidant personality, attention-deficit/hyperactivity (ADHD), and antisocial personality symptoms were measured with the Adult Self Report in 1805 mothers and 1361 fathers of 1866 children with a psychiatric diagnosis as assessed in a child and adolescent psychiatric outpatient clinic. In a multivariate model, including all parental symptom scores as outcome variables, all offspring psychiatric diagnoses, offspring comorbidity and age, parental age, parental educational attainment, employment, and relationship status were simultaneously tested as predictors. Both 35.7\% of mothers and 32.8\% of fathers scored (sub)clinical for at least one symptom domain, mainly depressive symptoms, ADHD symptoms or, only in fathers, avoidant personality symptoms. Parental psychiatric symptoms were predicted by unemployment. Parental depressive and ADHD symptoms were further predicted by offspring depression and offspring ADHD, respectively, as well as by not living together with the other parent. Finally, parental avoidant personality symptoms were also predicted by offspring autism spectrum disorders. In families with children referred to child and adolescent psychiatric outpatient clinics, parental symptom scores are associated with adverse circumstances and with similar psychopathology in their offspring. This signifies, without implying causality, that some families are particularly vulnerable, with multiple family members affected and living in adverse circumstances.

}, keywords = {Childhood psychopathology, Family circumstances, Parent-offspring associations, Parental psychopathology, Risk factors}, doi = {10.1007/s00787-018-1156-6}, author = {Wesseldijk, L W and Dieleman, G C and van Steensel, F J A and Bartels, M and Hudziak, J J and Lindauer, R J L and B{\"o}gels, S M and Middeldorp, C M} } @article {283, title = {Unraveling the Genetic and Environmental Relationship Between Well-Being and Depressive Symptoms Throughout the Lifespan}, journal = {Frontiers in Psychiatry}, volume = {9}, year = {2018}, pages = {261}, abstract = {

Whether well-being and depressive symptoms can be considered as two sides of the same coin is widely debated. The aim of this study was to gain insight into the etiology of the association between well-being and depressive symptoms across the lifespan. In a large twin-design, including data from 43,427 twins between age 7 and 99, we estimated the association between well-being and depressive symptoms throughout the lifespan and assessed genetic and environmental contributions to the observed overlap. For both well-being (range 31\% \–47\%) and depressive symptoms (range 50\%-61\%), genetic factors explained a substantial part of the phenotypic variance across the lifespan. Phenotypic correlations between well-being and depressive symptoms across ages ranged from -.34 in childhood to -.49 in adulthood. In children, genetic effects explained 49\% of the phenotypic correlation while in adolescents and young adults, genetic effects explained 60\% to 77\% of the phenotypic correlations. Moderate to high genetic correlations (ranging from -0.60 to -0.66) were observed in adolescence and adulthood, while in childhood environmental correlations were substantial but genetic correlations small. Our results suggest that in childhood genetic and environmental effects are about equally important in explaining the relationship between well-being and depressive symptoms. From adolescence onwards, the role of genetic effects increases compared to environmental effects. These results provided more insights into the etiological underpinnings of well-being and depressive symptoms, possibly allowing to articulate better strategies for health promotion and resource allocation in the future.

}, issn = {1664-0640}, doi = {10.3389/fpsyt.2018.00261}, url = {https://www.frontiersin.org/article/10.3389/fpsyt.2018.00261}, author = {Bart M. L. Baselmans and Willems, Yayouk E. and Catharina E. M. van Beijsterveldt and Lannie Ligthart and Gonneke Willemsen and Conor V Dolan and Dorret I. Boomsma and Meike Bartels} } @article {267, title = {ADHD Medication and Substance-Related Problems}, journal = {American Journal of Psychiatry}, volume = {174}, year = {2017}, pages = {877-885}, abstract = {

Objective: substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and long-term associations between ADHD medication treatment and substance-related events.

Method: the authors analyzed 2005\–2014 commercial health care claims from 2,993,887 (47.2\% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not.

Results: in adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35\% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95\% CI=0.64\–0.67), and female patients had 31\% lower odds of concurrent substance-related events (odds ratio=0.69, 95\% CI=0.67\–0.71). Moreover, male patients had 19\% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95\% CI=0.78\–0.85), and female patients had 14\% lower odds of substance-related events 2 years after medication periods (odds ratio=0.86, 95\% CI= 0.82\–0.91). Sensitivity analyses supported most findings but were less consistent for long-term associations among women.

Conclusions: these results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events.

}, doi = {10.1176/appi.ajp.2017.16060686}, url = {https://doi.org/10.1176/appi.ajp.2017.16060686}, author = {Quinn, Patrick D. and Chang, Zheng and Hur, Kwan and Gibbons, Robert D. and Benjamin B Lahey and Rickert, Martin E. and Sj{\"o}lander, Arvid and Lichtenstein, Paul and Henrik Larsson and D{\textquoteright}Onofrio, Brian M.} } @article {192, title = {Disentangling Heterogeneity of Childhood Disruptive Behavior Problems Into Dimensions and Subgroups}, journal = {American Academy of Child and Adolescent Psychiatry. Journal}, volume = {56}, year = {2017}, pages = {678{\textendash}686}, abstract = {

OBJECTIVE:

Irritable and oppositional behaviors are increasingly considered as distinct dimensions of oppositional defiant disorder. However, few studies have explored this multidimensionality across the broader spectrum of disruptive behavior problems (DBPs). This study examined the presence of dimensions and distinct subgroups of childhood DBPs, and the cross-sectional and longitudinal associations between these dimensions.

METHOD:

Using factor mixture models (FMMs), the presence of dimensions and subgroups of DBPs was assessed in the Generation R Study at ages 6 (n\ = 6,209) and 10 (n\ =\ 4,724) years. Replications were performed in two population-based cohorts (Netherlands Twin Registry, n\ = 4,402, and Swedish Twin Study of Child and Adolescent Development, n\ = 1,089) and a clinical sample (n\ = 1,933). We used cross-lagged modeling in the Generation R Study to assess cross-sectional and longitudinal associations between dimensions. DBPs were assessed using mother-reported responses to the Child Behavior Checklist.

RESULTS:

Empirically obtained dimensions of DBPs were oppositional behavior (age 6 years), disobedient behavior, rule-breaking behavior (age 10 years), physical aggression, and irritability (both ages). FMMs suggested that one-class solutions had the best model fit for all dimensions in all three population-based cohorts. Similar results were obtained in the clinical sample. All three dimensions, including irritability, predicted subsequent physical aggression (range, 0.08-0.16).

CONCLUSION:

This study showed that childhood DBPs should be regarded as a multidimensional phenotype rather than comprising distinct subgroups. Incorporating multidimensionality will improve diagnostic accuracy and refine treatment. Future studies need to address the biological validity of the DBP dimensions observed in this study; herein lies an important opportunity for neuroimaging and genetic measures.

}, doi = {10.1016/j.jaac.2017.05.019}, author = {Koen Bolhuis and Gitta Lubke and van der Ende, Jan and Meike Bartels and van Beijsterveldt, Toos and Paul Lichtenstein and Henrik Larsson and Vincent W.V. Jaddoe and Steven A. Kushner and Frank Verhulst and Dorret I. Boomsma and Henning Tiemeier} } @article {201, title = {Externalizing problems in childhood and adolescence predict subsequent educational achievement but for different genetic and environmental reasons}, journal = {Journal of Child Psychology and Psychiatry}, volume = {58}, year = {2017}, pages = {292{\textendash}304}, abstract = {

Background

Childhood behavior problems predict subsequent educational achievement; however, little research has examined the etiology of these links using a longitudinal twin design. Moreover, it is unknown whether genetic and environmental innovations provide incremental prediction for educational achievement from childhood to adolescence.

Methods

We examined genetic and environmental influences on parental ratings of behavior problems across childhood (age 4) and adolescence (ages 12 and 16) as predictors of educational achievement at age 16 using a longitudinal classical twin design.

Results

Shared-environmental influences on anxiety, conduct problems, and peer problems at age 4 predicted educational achievement at age 16. Genetic influences on the externalizing behaviors of conduct problems and hyperactivity at age 4 predicted educational achievement at age 16. Moreover, novel genetic and (to a lesser extent) nonshared-environmental influences acting on conduct problems and hyperactivity emerged at ages 12 and 16, adding to the genetic prediction from age 4.

Conclusions

These findings demonstrate that genetic and shared-environmental factors underpinning behavior problems in early childhood predict educational achievement in midadolescence. These findings are consistent with the notion that early-childhood behavior problems reflect the initiation of a life-course persistent trajectory with concomitant implications for social attainment. However, we also find evidence that genetic and nonshared-environment innovations acting on behavior problems have implications for subsequent educational achievement, consistent with recent work arguing that adolescence represents a sensitive period for socioaffective development.

}, keywords = {behavior problems, Education, genetics, longitudinal, Strengths and Difficulties Questionnaire, twin study}, issn = {1469-7610}, doi = {10.1111/jcpp.12655}, url = {http://dx.doi.org/10.1111/jcpp.12655}, author = {Lewis, Gary J. and Asbury, Kathryn and Robert Plomin} } @article {197, title = {Fine mapping genetic associations between the HLA region and extremely high intelligence}, journal = {Scientific Reports}, volume = {7}, year = {2017}, month = {2017}, pages = {41182}, abstract = {

General cognitive ability (intelligence) is one of the most heritable behavioural traits and most predictive of socially important outcomes and health. We hypothesized that some of the missing heritability of IQ might lie hidden in the human leukocyte antigen (HLA) region, which plays a critical role in many diseases and traits but is not well tagged in conventional GWAS. Using a uniquely powered design, we investigated whether fine-mapping of the HLA region could narrow the missing heritability gap. Our case-control design included 1,393 cases with extremely high intelligence scores (top 0.0003 of the population equivalent to IQ\ \>\ 147) and 3,253 unselected population controls. We imputed variants in 200 genes across the HLA region, one SNP (rs444921) reached our criterion for study-wide significance. SNP-based heritability of the HLA variants was small and not significant (h(2)\ =\ 0.3\%, SE\ =\ 0.2\%). A polygenic score from the case-control genetic association analysis of SNPs in the HLA region did not significantly predict individual differences in intelligence in an independent unselected sample. We conclude that although genetic variation in the HLA region is important to the aetiology of many disorders, it does not appear to be hiding much of the missing heritability of intelligence.

}, isbn = {2045-2322}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259706/}, author = {Zabaneh, Delilah and Eva Krapohl and Simpson, Michael A and Miller, Mike B and Iacono, William G and McGue, Matt and Putallaz, Martha and Lubinski, David and Robert Plomin and Breen, Gerome} } @article {194, title = {Genetic and environmental influences on conduct and antisocial personality problems in childhood, adolescence, and adulthood}, journal = {European Child {\&} Adolescent Psychiatry}, year = {2017}, month = {Jun}, abstract = {

Conduct problems in children and adolescents can predict antisocial personality disorder and related problems, such as crime and conviction. We sought an explanation for such predictions by performing a genetic longitudinal analysis. We estimated the effects of genetic, shared environmental, and unique environmental factors on variation in conduct problems measured at childhood and adolescence and antisocial personality problems measured at adulthood and on the covariation across ages. We also tested whether these estimates differed by sex. Longitudinal data were collected in the Netherlands Twin Register over a period of 27\ years. Age appropriate and comparable measures of conduct and antisocial personality problems, assessed with the Achenbach System of Empirically Based Assessment, were available for 9783 9\–10-year-old, 6839 13\–18-year-old, and 7909 19\–65-year-old twin pairs, respectively; 5114 twins have two or more assessments. At all ages, men scored higher than women. There were no sex differences in the estimates of the genetic and environmental influences. During childhood, genetic and environmental factors shared by children in families explained 43 and 44{\%} of the variance of conduct problems, with the remaining variance due to unique environment. During adolescence and adulthood, genetic and unique environmental factors equally explained the variation. Longitudinal correlations across age varied between 0.20 and 0.38 and were mainly due to stable genetic factors. We conclude that shared environment is mainly of importance during childhood, while genetic factors contribute to variation in conduct and antisocial personality problems at all ages, and also underlie its stability over age.

}, issn = {1435-165X}, doi = {10.1007/s00787-017-1014-y}, url = {https://doi.org/10.1007/s00787-017-1014-y}, author = {Laura W. Wesseldijk and Meike Bartels and Vink, Jacqueline M. and Catharina E. M. van Beijsterveldt and Lannie Ligthart and Dorret I. Boomsma and Christel Middeldorp} } @article {199, title = {Predicting educational achievement from DNA}, journal = {Mol Psychiatry}, volume = {22}, year = {2017}, month = {2017/02//print}, pages = {267 - 272}, abstract = {

A genome-wide polygenic score (GPS), derived from a 2013 genome-wide association study (N=127,000), explained 2\% of the variance in total years of education (EduYears). In a follow-up study (N=329,000), a new EduYears GPS explains up to 4\%. Here, we tested the association between this latest EduYears GPS and educational achievement scores at ages 7, 12 and 16 in an independent sample of 5825 UK individuals. We found that EduYears GPS explained greater amounts of variance in educational achievement over time, up to 9\% at age 16, accounting for 15\% of the heritable variance. This is the strongest GPS prediction to date for quantitative behavioral traits. Individuals in the highest and lowest GPS septiles differed by a whole school grade at age 16. Furthermore, EduYears GPS was associated with general cognitive ability (~3.5\%) and family socioeconomic status (~7\%). There was no evidence of an interaction between EduYears GPS and family socioeconomic status on educational achievement or on general cognitive ability. These results are a harbinger of future widespread use of GPS to predict genetic risk and resilience in the social and behavioral sciences.

}, isbn = {1359-4184}, url = {http://dx.doi.org/10.1038/mp.2016.107}, author = {Saskia Selzam and Eva Krapohl and Sophie von Stumm and Paul F O{\textquoteright}Reilly and Kaili Rimfeld and Yulia Kovas and Philip S. Dale and Lee,J J and Robert Plomin} } @article {256, title = {Predictive validity of parent- and self-rated ADHD symptoms in adolescence on adverse socioeconomic and health outcomes}, journal = {European Child {\&} Adolescent Psychiatry}, volume = {26}, year = {2017}, month = {Jul}, pages = {857{\textendash}867}, abstract = {

There is scarcity of research investigating the validity of self-report of attention deficit hyperactivity disorder (ADHD) symptoms compared to other informants, such as parents. This study aimed to compare the predictive associations of ADHD symptoms rated by parents and their children across adolescence on a range of adverse socioeconomic and health outcomes in early adulthood. Parent- and self-rated ADHD symptoms were assessed in 2960 individuals in early (13\–14\ years) and late adolescence (16\–17\ years). Logistic regression analyses were used to compare the associations between parent- and self-rated ADHD symptoms at both time points and adverse life outcomes in young adulthood obtained from Swedish national registries. Both parent- and self-ratings of ADHD symptoms were associated with increased risk for adverse outcomes, although associations of parent-ratings were more often statistically significant and were generally stronger (OR\ =\ 1.12\–1.49, p\ \<\ 0.05) than self-ratings (OR\ =\ 1.07\–1.17, p\ \<\ 0.05). After controlling for the other informant, parent-ratings of ADHD symptoms in both early and late adolescence significantly predicted academic and occupational failure, criminal convictions and traffic-related injuries, while self-ratings of ADHD symptoms only in late adolescence predicted substance use disorder and academic failure. Our findings suggest that both parent- and self-ratings of ADHD symptoms in adolescence provides valuable information on risk of future adverse socioeconomic and health outcomes, however, self-ratings are not valuable once parent-ratings have been taken into account in predicting most outcomes. Thus, clinicians and researchers should prioritize parent-ratings over self-ratings.

}, issn = {1435-165X}, doi = {10.1007/s00787-017-0957-3}, url = {https://doi.org/10.1007/s00787-017-0957-3}, author = {Du Rietz, Ebba and Kuja-Halkola, Ralf and Brikell, Isabell and Jangmo, Andreas and Sariaslan, Amir and Lichtenstein, Paul and Kuntsi, Jonna and Henrik Larsson} } @article {211, title = {Selected Lectures of the 13th International Workshop on Neonatology. LECT 39, Self-reported aggressive behavior in humans and biomarkers: a focus on lipids and methylation}, journal = {Journal of Pediatric and Neonatal Individualized Medicine (JPNIM)}, volume = {6}, year = {2017}, month = {10/2017}, pages = {52-55}, type = {Proceedings of the 13{\textdegree} International Workshop on Neonatology, Twins: identical but different, Cagliari (Italy), October 25-28}, abstract = {

PDF Available here

}, keywords = {13th International Workshop on Neonatology, 2017, Aggression, Cagliari}, doi = {10.7363/060235}, url = {http://www.jpnim.com/index.php/jpnim/article/view/060235/467}, author = {Fiona Hagenbeek and Jenny van Dongen and Kluft, Cornelis and Lannie Ligthart} } @article {190, title = {Sum Scores in Twin Growth Curve Models: Practicality Versus Bias}, journal = {Behavior Genetics}, volume = {47}, year = {2017}, month = {9}, pages = {516{\textendash}536}, abstract = {

To study behavioral or psychiatric phenotypes, multiple indices of the behavior or disorder are often collected that are thought to best reflect the phenotype. Combining these items into a single score (e.g. a sum score) is a simple and practical approach for modeling such data, but this simplicity can come at a cost in longitudinal studies, where the relevance of individual items often changes as a function of age. Such changes violate the assumptions of longitudinal measurement invariance (MI), and this violation has the potential to obfuscate the interpretation of the results of latent growth models fit to sum scores. The objectives of this study are (1) to investigate the extent to which violations of longitudinal MI lead to bias in parameter estimates of the average growth curve trajectory, and (2) whether absence of MI affects estimates of the heritability of these growth curve parameters. To this end, we analytically derive the bias in the estimated means and variances of the latent growth factors fit to sum scores when the assumption of longitudinal MI is violated. This bias is further quantified via Monte Carlo simulation, and is illustrated in an empirical analysis of aggression in children aged 3\–12\ years. These analyses show that measurement non-invariance across age can indeed bias growth curve mean and variance estimates, and our quantification of this bias permits researchers to weigh the costs of using a simple sum score in longitudinal studies. Simulation results indicate that the genetic variance decomposition of growth factors is, however, not biased due to measurement non-invariance across age, provided the phenotype is measurement invariant across birth-order and zygosity in twins.

}, issn = {0001-8244}, doi = {10.1007/s10519-017-9864-0}, url = {https://doi.org/10.1007/s10519-017-9864-0}, author = {Luningham, Justin M. and Daniel B. McArtor and Meike Bartels and Dorret I. Boomsma and Gitta Lubke} } @article {253, title = {Childhood attention-deficit/hyperactivity disorder symptoms and the development of adolescent alcohol problems: A prospective, population-based study of Swedish twins}, journal = {American Journal of Medical Genetics Part B: Neuropsychiatric Genetics}, volume = {171}, year = {2016}, pages = {958-970}, abstract = {

Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of problematic alcohol and other substance use in adolescence. This study used data from an ongoing, prospective, population-based twin study of Swedish children and adolescents to evaluate the extent to which the association between ADHD symptoms and alcohol problems reflects a unique source of genetic or environmental risk related to ADHD versus a broader predisposition to youth externalizing behavior. We used all available data from same-sex monozygotic (MZ) and dizygotic (DZ) twins on ADHD symptoms in childhood (age 9/12; N\ =\ 15,549) and alcohol problems in late adolescence (age 18; N\ =\ 2,564). Consistent with prior longitudinal studies, the phenotypic association between hyperactive/impulsive ADHD symptoms and alcohol problems was small in magnitude, whereas the association for inattentive symptoms was even weaker. Additive genetic influences explained 99.8\% of the association between hyperactive/impulsive symptoms and alcohol problems. Furthermore, we found that the genetic risk specifically associated with hyperactive/impulsive symptoms was attenuated when estimated in the context of externalizing behavior liability during childhood, of which ADHD symptoms were specific expressions. In sensitivity analyses exploring hyperactivity in mid-adolescence, we found a similar pattern of genetic associations. These results are consistent with previous findings of genetically driven overlap in the etiology of ADHD and problematic alcohol use. At least some of this co-occurrence may result from a general predisposition to externalizing behaviors in youth. \© 2015 Wiley Periodicals, Inc.

}, keywords = {ADHD, behavioral genetics, externalizing, neurodevelopmental problems, substance misuse}, doi = {10.1002/ajmg.b.32412}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.b.32412}, author = {Quinn, Patrick D. and Erik Pettersson and Lundstr{\"o}m, Sebastian and Anckars{\"a}ter, Henrik and L{\r a}ngstr{\"o}m, Niklas and Gumpert, Clara Hellner and Henrik Larsson and Lichtenstein, Paul and D{\textquoteright}Onofrio, Brian M.} } @article {129, title = {Discovery of biochemical biomarkers for aggression: A role for metabolomics in psychiatry.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, year = {2016}, month = {2016 Feb 23}, abstract = {

Human aggression encompasses a wide range of behaviors and is related to many psychiatric disorders. We introduce the different classification systems of aggression and related disorders as a basis for discussing biochemical biomarkers and then present an overview of studies in humans (published between 1990 and 2015) that reported statistically significant associations of biochemical biomarkers with aggression, DSM-IV disorders involving aggression, and their subtypes. The markers are of different types, including inflammation markers, neurotransmitters, lipoproteins, and hormones from various classes. Most studies focused on only a limited portfolio of biomarkers, frequently a specific class only. When integrating the data, it is clear that compounds from several biological pathways have been found to be associated with aggressive behavior, indicating complexity and the need for a broad approach. In the second part of the paper, using examples from the aggression literature and psychiatric metabolomics studies, we argue that a better understanding of aggression would benefit from a more holistic approach such as provided by metabolomics. \© 2016 Wiley Periodicals, Inc.

}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32435}, author = {Fiona Hagenbeek and Kluft, Cornelis and Thomas Hankemeier and Meike Bartels and Draisma, Harmen H M and Christel Middeldorp and Berger, Ruud and Antonio Noto and Lussu, Milena and Pool, Ren{\'e} and Faa, Gavino and Dorret I. Boomsma} } @article {248, title = {Inference Based on the Best-Fitting Model Can Contribute to the Replication Crisis: Assessing Model Selection Uncertainty Using a Bootstrap Approach}, journal = {Structural Equation Modeling: A Multidisciplinary Journal}, volume = {23}, year = {2016}, pages = {479-490}, abstract = {

Inferences and conclusions drawn from model fitting analyses are commonly based on a single \“best fitting\” model. If model selection and inference are carried out using the same data model selection, uncertainty is ignored. We illustrate the Type I error inflation that can result from using the same data for model selection and inference, and we then propose a simple bootstrap-based approach to quantify model selection uncertainty in terms of model selection rates. A selection rate can be interpreted as an estimate of the replication probability of a fitted model. The benefits of bootstrapping model selection uncertainty are demonstrated in growth mixture analyses of data from the National Longitudinal Study of Youth, and a 2-group measurement invariance analysis of the Holzinger\–Swineford data.

}, doi = {10.1080/10705511.2016.1141355}, url = {https://doi.org/10.1080/10705511.2016.1141355}, author = {Gitta Lubke and Ian Campbell} } @article {264, title = {Joint developmental trajectories of internalizing and externalizing disorders between childhood and adolescence}, journal = {Development and Psychopathology}, volume = {-1}, year = {2016}, month = {07}, pages = {1-10}, abstract = {

This study sought to identify trajectories of DSM-IV based internalizing (INT) and externalizing (EXT) problem scores across childhood and adolescence and to provide insight into the comorbidity by modeling the co-occurrence of INT and EXT trajectories. INT and EXT were measured repeatedly between age 7 and age 15 years in over 7,000 children and analyzed using growth mixture models. Five trajectories were identified for both INT and EXT, including very low, low, decreasing, and increasing trajectories. In addition, an adolescent onset trajectory was identified for INT and a stable high trajectory was identified for EXT. Multinomial regression showed that similar EXT and INT trajectories were associated. However, the adolescent onset INT trajectory was independent of high EXT trajectories, and persisting EXT was mainly associated with decreasing INT. Sex and early life environmental risk factors predicted EXT and, to a lesser extent, INT trajectories. The association between trajectories indicates the need to consider comorbidity when a child presents with INT or EXT disorders, particularly when symptoms start early. This is less necessary when INT symptoms start at adolescence. Future studies should investigate the etiology of co-occurring INT and EXT and the specific treatment needs of these severely affected children.

}, doi = {10.1017/S0954579416000572}, author = {Michel G. Nivard and Gitta Lubke and Conor V Dolan and David M Evans and St. Pourcain, B and R. Munaf{\`o}, Marcus and Christel Middeldorp} } @article {102, title = {Longitudinal heritability of childhood aggression.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, year = {2016}, month = {2016 Jan 19}, abstract = {

The genetic and environmental contributions to the variation and longitudinal stability in childhood aggressive behavior were assessed in two large twin cohorts, the Netherlands Twin Register (NTR), and the Twins Early Development Study (TEDS; United Kingdom). In NTR, maternal ratings on aggression from the Child Behavior Checklist (CBCL) were available for 10,765 twin pairs at age 7, for 8,557 twin pairs at age 9/10, and for 7,176 twin pairs at age 12. In TEDS, parental ratings of conduct disorder from the Strength and Difficulty Questionnaire (SDQ) were available for 6,897 twin pairs at age 7, for 3,028 twin pairs at age 9 and for 5,716 twin pairs at age 12. In both studies, stability and heritability of aggressive behavioral problems was high. Heritability was on average somewhat, but significantly, lower in TEDS (around 60\%) than in NTR (between 50\% and 80\%) and sex differences were slightly larger in the NTR sample. In both studies, the influence of shared environment was similar: in boys shared environment explained around 20\% of the variation in aggression across all ages while in girls its influence was absent around age 7 and only came into play at later ages. Longitudinal genetic correlations were the main reason for stability of aggressive behavior. Individual differences in CBCL-Aggressive Behavior and SDQ-Conduct disorder throughout childhood are driven by a comparable but significantly different genetic architecture. \© 2016 Wiley Periodicals, Inc.

}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32420}, author = {Porsch, Robert M and Christel Middeldorp and Cherny, Stacey S and Eva Krapohl and Catharina E. M. van Beijsterveldt and Loukola, Anu and Korhonen, Tellervo and Pulkkinen, Lea and Corley, Robin and Rhee, Soo and Kaprio, Jaakko and Rose, Richard R and Hewitt, John K and Sham, Pak and Robert Plomin and Dorret I. Boomsma and Meike Bartels} } @article {265, title = {Relative Immaturity in Childhood and Attention-Deficit/Hyperactivity Disorder Symptoms From Childhood to Early Adulthood: Exploring Genetic and Environmental Overlap Across Development}, journal = {Journal of the American Academy of Child \& Adolescent PsychiatryJournal of the American Academy of Child \& Adolescent Psychiatry}, volume = {55}, year = {2016}, month = {2016/10/01}, pages = {886 - 895}, abstract = {

ObjectiveAttention-deficit/hyperactivity disorder (ADHD) has been linked to immaturity relative to peers in childhood, yet it is unclear how such immaturity is associated with ADHD across development. This longitudinal twin study examined the genetic and environmental contributions to the association between parents? perception of their child?s immaturity relative to peers (RI) in childhood and ADHD symptoms across development.ObjectiveAttention-deficit/hyperactivity disorder (ADHD) has been linked to immaturity relative to peers in childhood, yet it is unclear how such immaturity is associated with ADHD across development. This longitudinal twin study examined the genetic and environmental contributions to the association between parents? perception of their child?s immaturity relative to peers (RI) in childhood and ADHD symptoms across development.

}, isbn = {0890-8567}, url = {https://doi.org/10.1016/j.jaac.2016.06.014}, author = {Brikell, Isabell and Kuja-Halkola, Ralf and Larsson, Jan-Olov and Benjamin B Lahey and Kuntsi, Jonna and Lichtenstein, Paul and Rydelius, Per-Anders and Henrik Larsson} } @article {257, title = {Role of overlapping genetic and environmental factors in the relationship between early adolescent conduct problems and substance use in young adulthood}, journal = {Addiction (Abingdon, England)}, volume = {111}, year = {2016}, month = {2016/06/}, pages = {1036 - 1045}, abstract = {

AIMS: To determine (1) the prospective associations of conduct problems during early adolescence with tobacco, alcohol and cannabis use in young adulthood and (2) to what extent these associations are due to overlapping genetic versus environmental influences. DESIGN: A prospective twin study using biometric twin modelling. SETTING: Finland. PARTICIPANTS: A total of 1847 Finnish twins (943 males and 904 females) were interviewed in early adolescence, 73\% of whom (n\ =\ 1353, 640 males and 713 females) were retained in young adulthood. MEASUREMENTS: Symptom counts of conduct disorder (CD) criteria were obtained from a semi-structured clinical interview in early adolescence [age 14-15 years, mean\ =\ 14.2, standard deviation (SD)\ =\ 0.15]. Frequency of alcohol, tobacco and cannabis use was obtained from a semi-structured clinical interview in young adulthood (age 19.9-26.6 years, mean\ =\ 22.4, SD\ =\ 0.7). FINDINGS: We found modest to moderate phenotypical correlations (r\ =\ 0.16-0.35) between early adolescent CD symptoms and substance use in young adulthood. In males, the phenotypical correlations of CD symptoms with all three substance use variables are explained largely by overlapping genetic influences. In females, overlapping shared environmental influences predominantly explain the phenotypical correlation between CD symptoms and tobacco and cannabis use. CONCLUSIONS: Conduct disorder symptoms in early adolescence appear to moderately predict substance use in early adulthood. In males, genetic influences seem to be most important in explaining the relationship between conduct disorder symptoms and substance use whereas in females, shared environmental influences seem to be most important.

}, isbn = {1360-04430965-2140}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26748618}, author = {Verweij, Karin J H and Creemers, Hanneke E and Korhonen, Tellervo and Latvala, Antti and Dick, Danielle M and Richard J. Rose and Huizink, Anja C and Kaprio, Jaakko} } @article {258, title = {Spousal resemblance in psychopathology: A comparison of parents of children with and without psychopathology}, journal = {European PsychiatryEuropean Psychiatry}, volume = {34}, year = {2016}, month = {2016/04/01}, pages = {49 - 55}, abstract = {

BACKGROUND:

Spouses resemble each other for psychopathology, but data regarding spousal resemblance in externalizing psychopathology, and data regarding spousal resemblance across different syndromes (e.g. anxiety in wives and attention deficit/hyperactivity disorder [ADHD] in husbands) are limited. Moreover, knowledge is lacking regarding spousal resemblance in parents of children with psychiatric disorders. We investigated and compared spousal resemblance within and across internalizing and externalizing symptom domains in parents of children with and without psychopathology.

METHODS:

Symptoms of depression, anxiety, avoidant personality, ADHD, and antisocial personality were assessed with the Adult Self Report in 728 mothers and 544 fathers of 778 children seen in child and adolescent psychiatric outpatient clinics and in 2075 mothers and 1623 fathers of 2784 children from a population-based sample. Differences in symptom scores and spousal correlations between the samples were tested.

RESULTS:

Parents in the clinical sample had higher symptom scores than in the population-based sample. In both samples, correlations within and across internalizing and externalizing domains of psychopathology were significant. Importantly, correlations were significantly higher in the clinical sample (P=0.03). Correlations, within and across symptoms, ranged from 0.14 to 0.30 in the clinical sample and from 0.05 to 0.23 in the population-based sample.

CONCLUSIONS:

This large study shows that spousal resemblance is not only present within but also across symptom domains. Especially in the clinical sample, ADHD symptoms in fathers and antisocial personality symptoms in mothers were correlated with a range of psychiatric symptoms in their spouses. Clinicians need to be alert of these multiple affected families.

}, isbn = {0924-9338}, url = {https://doi.org/10.1016/j.eurpsy.2016.01.2423}, author = {Laura W. Wesseldijk and Dieleman, G.C. and Lindauer, R.J.L. and Meike Bartels and Gonneke Willemsen and J.J. Hudziak and Dorret I. Boomsma and Christel Middeldorp} } @article {81, title = {Antisocial behavior and polymorphisms in the oxytocin receptor gene: findings in two independent samples.}, journal = {Mol Psychiatry}, year = {2015}, month = {2015 Sep 22}, abstract = {

The quantitative genetic contribution to antisocial behavior is well established, but few, if any, genetic variants are established as risk factors. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may modulate interpersonal aggression. We here investigated whether single-nucleotide polymorphisms (SNPs) in the OXT receptor gene (OXTR) are associated with the expression of antisocial behavior. A discovery sample, including both sexes, was drawn from the Child and Adolescent Twin Study in Sweden (CATSS; n=2372), and a sample from the Twin Study of Child and Adolescent Development (TCHAD; n=1232) was used for replication. Eight SNPs in OXTR, selected on previous associations with social and antisocial behavior, were genotyped in the participants of CATSS. Significant polymorphisms were subsequently genotyped in TCHAD for replication. Participants completed self-assessment questionnaires-Life History of Aggression (LHA; available only in CATSS), and Self-Reported Delinquency (SRD; available in both samples)-designed to capture antisocial behavior as continuous traits. In the discovery sample, the rs7632287 AA genotype was associated with higher frequency of antisocial behavior in boys, and this was then replicated in the second sample. In particular, overt aggression (directly targeting another individual) was strongly associated with this genotype in boys (P=6.2 \× 10(-7) in the discovery sample). Meta-analysis of the results for antisocial behavior from both samples yielded P=2.5 \× 10(-5). Furthermore, an association between rs4564970 and LHA (P=0.00013) survived correction in the discovery sample, but there was no association with the SRD in the replication sample. We conclude that the rs7632287 and rs4564970 polymorphisms in OXTR may independently influence antisocial behavior in adolescent boys. Further replication of our results will be crucial to understanding how aberrant social behavior arises, and would support the OXT receptor as one potential target in the treatment of aggressive antisocial behavior.Molecular Psychiatry advance online publication, 22 September 2015; doi:10.1038/mp.2015.144.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.144}, author = {Hovey, D and Lindstedt, M and Zettergren, A and Jonsson, L and Johansson, A and Melke, J and Kerekes, N and Anckars{\"a}ter, H and Paul Lichtenstein and Lundstr{\"o}m, S and Westberg, L} } @article {94, title = {Epigenome-Wide Association Study of Aggressive Behavior}, journal = {Twin Research and Human Genetics}, volume = {FirstView}, year = {2015}, month = {11}, pages = {1{\textendash}13}, issn = {1839-2628}, doi = {10.1017/thg.2015.74}, url = {http://journals.cambridge.org/article_S1832427415000742}, author = {Jenny van Dongen and Michel G. Nivard and Bart M. L. Baselmans and Zilh{\~a}o,Nuno R. and Lannie Ligthart and Bastiaan T. Heijmans and Meike Bartels and Dorret I. Boomsma} } @article {101, title = {A genome-wide approach to children{\textquoteright}s aggressive behavior: The EAGLE consortium.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, year = {2015}, month = {2015 Jun 18}, abstract = {

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children\&$\#$39;s aggressive behavior to date (N\ =\ 18,988), with measures in two developmental stages (N\ =\ 15,668 early childhood and N\ =\ 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children\&$\#$39;s aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54\%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P\ =\ 5.30\ \×\ 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. \© 2015 Wiley Periodicals, Inc.

}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32333}, author = {Pappa, Irene and St Pourcain, Beate and Benke, Kelly and Cavadino, Alana and Hakulinen, Christian and Michel G. Nivard and Nolte, Ilja M and Tiesler, Carla M T and Marian J Bakermans-Kranenburg and Gareth E Davies and David M Evans and Geoffroy, Marie-Claude and Grallert, Harald and Groen-Blokhuis, Maria M and J.J. Hudziak and Kemp, John P and Keltikangas-J{\"a}rvinen, Liisa and McMahon, George and Mileva-Seitz, Viara R and Motazedi, Ehsan and Power, Christine and Raitakari, Olli T and Ring, Susan M and Rivadeneira, Fernando and Rodriguez, Alina and Scheet, Paul A and Sepp{\"a}l{\"a}, Ilkka and Snieder, Harold and Standl, Marie and Thiering, Elisabeth and Timpson, Nicholas J and Veenstra, Ren{\'e} and Velders, Fleur P and Whitehouse, Andrew J O and Smith, George Davey and Heinrich, Joachim and Hypponen, Elina and Lehtim{\"a}ki, Terho and Christel Middeldorp and Oldehinkel, Albertine J and Pennell, Craig E and Dorret I. Boomsma and Henning Tiemeier} } @article {80, title = {A Longitudinal Study of Resting Heart Rate and Violent Criminality in More Than 700 000 Men.}, journal = {JAMA Psychiatry}, volume = {72}, year = {2015}, month = {2015 Oct 1}, pages = {971-8}, abstract = {

IMPORTANCE: Low resting heart rate is a well-replicated physiological correlate of aggressive and antisocial behavior in children and adolescents, but whether low resting heart rate increases the risk of violence and other antisocial and risk-taking behaviors in adulthood has not been studied in representative samples.

OBJECTIVE: To study the predictive association of resting heart rate with violent and nonviolent criminality and with fatal and nonfatal injuries owing to assaults and unintentional injuries in the population.

DESIGN, SETTING, AND PARTICIPANTS: We conducted a study of data from several Swedish national registers on 710 264 Swedish men in the general population born from 1958 to 1991, with a follow-up of up to 35.7 years. Outcome data were available and analyzed from January 1, 1973, through December 31, 2009. Resting heart rate was measured together with blood pressure at mandatory military conscription testing at a mean (SD) age of 18.2 (0.5) years.

MAIN OUTCOMES AND MEASURES: Violent and nonviolent criminal convictions and medical treatments or deaths owing to assaults and unintentional injuries.

RESULTS: In models adjusted for physical, cardiovascular, psychiatric, cognitive, and socioeconomic covariates, compared with 139 511 men in the highest quintile of the distribution of resting heart rate (\≥83 beats/min), 132 595 men with the lowest quintile (heart rate, \≤60 beats/min) had a 39\% (95\% CI, 35\%-44\%) higher hazard of being convicted of violent crimes and a 25\% (95\% CI, 23\%-28\%) higher hazard of being convicted of nonviolent crimes. The corresponding hazard was 39\% higher for assault injuries (95\% CI, 33\%-46\%) and for unintentional injuries (95\% CI, 38\%-41\%). Further adjustment for cardiorespiratory fitness in a subset of 572 610 men with data from an exercise test did not reduce the associations. Similar associations were found between low systolic blood pressure and violent and nonviolent criminality and for assault injuries when systolic blood pressure was studied instead of resting heart rate in more than 1 million men.

CONCLUSIONS AND RELEVANCE: Among men, low resting heart rate in late adolescence was associated with an increased risk for violent criminality, nonviolent criminality, exposure to assault, and unintentional injury in adulthood. Most of these results were replicated with low systolic blood pressure. Resting heart rate and other autonomic measures merit further study in the development and prevention of violence and antisocial behavior.

}, issn = {2168-6238}, doi = {10.1001/jamapsychiatry.2015.1165}, author = {Latvala, Antti and Kuja-Halkola, Ralf and Almqvist, Catarina and Henrik Larsson and Paul Lichtenstein} }