@article {470, title = {Genetics and epigenetics of human aggression}, journal = {Handbook of Clinical Neurology, Brain and Crime}, volume = {197}, year = {2023}, pages = {13{\textendash}44}, abstract = {

There is substantial variation between humans in aggressive behavior, with its biological etiology and molecular genetic basis mostly unknown. This review chapter offers an overview of genomic and omics studies revealing the genetic contribution to aggression and first insights into associations with epigenetic and other omics (e.g., metabolomics) profiles. We allowed for a broad phenotype definition including studies on \"aggression\", \"aggressive behavior\" or \"aggression-related traits\", \"antisocial behavior\", \"conduct disorder\", and \"oppositional defiant disorder\". Heritability estimates based on family and twin studies in children and adults of this broadly defined phenotype of aggression are around 50\%, with relatively small fluctuations around this estimate. Next, we review the genome-wide association studies (GWAS) which search for associations with alleles and also allow for gene-based tests and epigenome-wide association studies (EWAS) which seek to identify associations with differently methylated regions across the genome. Both GWAS and EWAS allow for construction of Polygenic and DNA methylation scores at an individual level. Currently, these predict a small percentage of variance in aggression. We expect that increases in sample size will lead to additional discoveries in GWAS and EWAS, and that multiomics approaches will lead to a more comprehensive understanding of the molecular underpinnings of aggression.

}, keywords = {Epigenome-wide association studies, Epigenomics, genome-wide association studies, Genomics, heritability, Human aggression}, doi = {10.1016/B978-0-12-821375-9.00005-0}, author = {Odintsova, Veronika V and Hagenbeek, Fiona A and Van der Laan, Camiel M and van de Weijer, Steve and Boomsma, Dorret I} } @article {457, title = {Heritability of urinary amines, organic acids, and steroid hormones in children}, journal = {Metabolites}, volume = {12}, year = {2022}, pages = {474}, abstract = {

Variation in metabolite levels reflects individual differences in genetic and environmental factors. Here, we investigated the role of these factors in urinary metabolomics data in children. We examined the effects of sex and age on 86 metabolites, as measured on three metabolomics platforms that target amines, organic acids, and steroid hormones. Next, we estimated their heritability in a twin cohort of 1300 twins (age range: 5.7-12.9 years). We observed associations between age and 50 metabolites and between sex and 21 metabolites. The monozygotic (MZ) and dizygotic (DZ) correlations for the urinary metabolites indicated a role for non-additive genetic factors for 50 amines, 13 organic acids, and 6 steroids. The average broad-sense heritability for these amines, organic acids, and steroids was 0.49 (range: 0.25-0.64), 0.50 (range: 0.33-0.62), and 0.64 (range: 0.43-0.81), respectively. For 6 amines, 7 organic acids, and 4 steroids the twin correlations indicated a role for shared environmental factors and the average narrow-sense heritability was 0.50 (range: 0.37-0.68), 0.50 (range; 0.23-0.61), and 0.47 (range: 0.32-0.70) for these amines, organic acids, and steroids. We conclude that urinary metabolites in children have substantial heritability, with similar estimates for amines and organic acids, and higher estimates for steroid hormones.

}, keywords = {amines, children, classical twin design, heritability, metabolites, organic acids, steroid hormones, urine}, doi = {10.3390/metabo12060474}, author = {Hagenbeek, Fiona A and van Dongen, Jenny and Pool, Ren{\'e} and Harms, Amy C and Roetman, Peter J and Fanos, Vassilios and van Keulen, Britt J and Walker, Brian R and Karu, Naama and Hulshoff Pol, Hilleke E and Rotteveel, Joost and Finken, Martijn J J and Vermeiren, Robert R J M and Kluft, Cornelis and Bartels, Meike and Hankemeier, Thomas and Boomsma, Dorret I} } @article {464, title = {Multivariate genetic structure of externalizing behavior and structural brain development in a longitudinal adolescent twin sample}, journal = {International Journal of Molecular Sciences}, volume = {23}, year = {2022}, pages = {3176}, abstract = {

Externalizing behavior in its more extreme form is often considered a problem to the individual, their families, teachers, and society as a whole. Several brain structures have been linked to externalizing behavior and such associations may arise if the (co)development of externalizing behavior and brain structures share the same genetic and/or environmental factor(s). We assessed externalizing behavior with the Child Behavior Checklist and Youth Self Report, and the brain volumes and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]) with magnetic resonance imaging in the BrainSCALE cohort, which consisted of twins and their older siblings from 112 families measured longitudinally at ages 10, 13, and 18 years for the twins. Genetic covariance modeling based on the classical twin design, extended to also include siblings of twins, showed that genes influence externalizing behavior and changes therein (h2 up to 88\%). More pronounced externalizing behavior was associated with higher FA (observed correlation rph up to +0.20) and lower MD (rph up to -0.20), with sizeable genetic correlations (FA ra up to +0.42; MD ra up to -0.33). The cortical gray matter (CGM; rph up to -0.20) and cerebral white matter (CWM; rph up to +0.20) volume were phenotypically but not genetically associated with externalizing behavior. These results suggest a potential mediating role for global brain structures in the display of externalizing behavior during adolescence that are both partially explained by the influence of the same genetic factor.

}, keywords = {Adolescence, externalizing behavior, Genetic correlation, gray matter volume, heritability, longitudinal, magnetic resonance imaging, white matter integrity}, doi = {10.3390/ijms23063176}, author = {Teeuw, Jalmar and Klein, Marieke and Mota, Nina Roth and Brouwer, Rachel M and van {\textquoteright}t Ent, Dennis and Al-Hassaan, Zyneb and Franke, Barbara and Boomsma, Dorret I and Hulshoff Pol, Hilleke E} } @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} } @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 {430, title = {An extended twin-pedigree study of different classes of voluntary exercise behavior}, journal = {Behavior Genetics}, volume = {50}, year = {2020}, pages = {94{\textendash}104}, abstract = {

We investigated the familial clustering of different classes of voluntary regular exercise behavior in extended twin-family pedigrees. In contrast to the earlier work based on twin data only, this allowed us to estimate the contributions of shared household effects (C), additive (A), and non-additive (D) genetic effects on voluntary exercise behavior. To test whether shared household effects were inflated by assortative mating we examined the causes of spousal resemblance. For adolescent and adult participants (aged 16 to 65) in the Netherlands Twin Register we constructed 19,543 pedigrees which specified all relations among nuclear family members and larger families in the register (N = 50,690 individuals). Data were available on total weekly MET minutes spent on leisure time exercise, and on total weekly MET minutes spent on exercise activities in team-based, solitary, competitive, non-competitive, externally paced and internally paced exercise. We analyzed the data in the Mendel software package (Lange et al. in Bioinformatics 29(12):1568-1570, 2013) under multiple definitions of household sharing and used data from spouses of twins to test phenotypic assortment, social homogamy, and marital interaction as potential sources of spousal resemblance. Results confirmed the influence of genetic factors on the total volume of weekly exercise behavior throughout the life span. Broad sense heritability ranged from 34 to 41\% (19-26\% A, 12-21\% D), and did not depend on the definition for household sharing. Engaging in team-based, competitive, externally paced activities (e.g., soccer) was \  13\% more heritable than engaging in non-competitive, solitary activities (e.g., jogging). Having shared a household as siblings explained 4-8\% of the variance in adult exercise behavior, whereas sharing a household by spouses yielded higher C estimates (20-24\%), as it incorporates spousal resemblance. Spousal resemblance was explained by both social homogamy and marital interaction, with little evidence for phenotypic assortment. We conclude that both the amount of voluntary exercise behavior and the preference for specific classes of exercise activities in adults is explained by additive and non-additive genetic factors and unique environmental influences that include correlated exercise behavior of spouses.

}, keywords = {Exercise behavior, heritability, Household, Pedigree, Spousal resemblance, twins}, doi = {10.1007/s10519-019-09990-7}, author = {van der Zee, Matthijs D and Helmer, Q and Boomsma, D I and Dolan, C V and de Geus, E J C} } @article {424, title = {Genetics and not shared environment explains familial resemblance in adult metabolomics data}, journal = {Human Genetics}, volume = {23}, year = {2020}, pages = {145{\textendash}155}, abstract = {

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term \&$\#$39;metabolomics\&$\#$39; refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.

}, keywords = {classical twin design, enrichment analysis, heritability, metabolite classes, shared environment}, doi = {DOI: 10.1017/thg.2020.53}, author = {Pool, Ren{\'e} and Hagenbeek, Fiona A and Hendriks, Anne M and van Dongen, Jenny and Willemsen, Gonneke and de Geus, Eco and BBMRI Metabolomics Consortium and Willems van Dijk, Ko and Verhoeven, Aswin and Suchiman, H Eka and Beekman, Marian and Slagboom, P Eline and Harms, Amy C and Hankemeier, Thomas and Boomsma, Dorret I} } @article {418, title = {Genetic and environmental influences on different forms of bullying perpetration, bullying victimization, and their co-occurrence}, journal = {Behavior Genetics}, volume = {49}, year = {2019}, pages = {432{\textendash}443}, abstract = {

Bullying comes in different forms, yet most previous genetically-sensitive studies have not distinguished between them. Given the serious consequences and the high prevalence of bullying, it is remarkable that the aetiology of bullying and its different forms has been under-researched. We present the first study to investigate the genetic architecture of bullying perpetration, bullying victimization, and their co-occurrence for verbal, physical and relational bullying. Primary-school teachers rated 8215 twin children on bullying perpetration and bullying victimization. For each form of bullying, we investigated, through genetic structural equation modelling, the genetic and environmental influences on being a bully, a victim or both. 34\% of the children were involved as bully, victim, or both. The correlation between being a bully and being a victim varied from 0.59 (relational) to 0.85 (physical). Heritability was \  70\% for perpetration and \  65\% for victimization, similar in girls and boys, yet both were somewhat lower for the relational form. Shared environmental influences were modest and more pronounced among girls. The correlation between being a bully and being a victim was explained mostly by genetic factors for verbal (\  71\%) and especially physical (\  77\%) and mostly by environmental factors for relational perpetration and victimization (\  60\%). Genes play a large role in explaining which children are at high risk of being a victim, bully, or both. For victimization this suggests an evocative gene-environment correlation: some children are at risk of being exposed to bullying, partly due to genetically influenced traits. So, genetic influences make some children more vulnerable to become a bully, victim or both.

}, keywords = {Bully-victims, Bullying, heritability, School, twins, Victimization}, doi = {10.1007/s10519-019-09968-5}, author = {Veldkamp, Sabine A M and Boomsma, Dorret I and de Zeeuw, Eveline L and van Beijsterveldt, Catharina E M and Bartels, Meike and Dolan, Conor V and van Bergen, Elsje} } @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 {95, title = {Methylation as an epigenetic source of random genetic effects in the classical twin design}, journal = {Advances in Genomics and Genetics, Dove Medical Press}, volume = {5}, year = {2015}, month = {09/2015}, pages = {305{\textendash}315}, abstract = {

The epigenetic effects of cytosine methylation on gene expression are an acknowledged source of phenotypic variance. The discordant monozygotic (MZ) twin design has been used to demonstrate the role of methylation in disease. Application of the classical twin design, featuring both monozygotic and dizygotic twins, has demonstrated that individual differences in methylation levels are attributable to genetic and environmental (including stochastic) factors, with the latter explaining most of the variance. What implications epigenetic sources of variance have for the twin modeling of (non-epigenetic) phenotypes such as height and IQ is an open question. One possibility is that epigenetic effects are absorbed by the variance component attributable to unshared environmental. Another possibility is that such effects form an independent source of variance distinguishable in principle from standard genetic and environmental sources. In the present paper, we conceptualized epigenetic processes as giving rise to randomness in the effects of polygenetic influences. This means that the regression coefficient in the regression of the phenotype on the polygenic factor, as specified in the twin model, varies over individuals. We investigate the consequences of ignoring this randomness in the standard twin model.

}, keywords = {classical twin design, epigenetics, heritability, methylation, parameter randomness}, doi = {http://dx.doi.org/10.2147/AGG.S46909}, url = {https://www.dovepress.com/methylation-as-an-epigenetic-source-of-random-genetic-effects-in-the-c-peer-reviewed-article-AGG}, author = {Conor V Dolan and Michel G. Nivard and Jenny van Dongen and van der Sluis,Sophie and Dorret I. Boomsma} }