A genome-wide approach to children's aggressive behavior: The EAGLE consortium (original) (raw)
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Genetic Association Study of Childhood Aggression across raters, instruments and age
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 ass...
Polygenic risk for aggressive behaviour from late childhood through early adulthood
2021
Twin studies suggest a substantial role for genes in explaining individual differences in aggressive behavior across development. It is unclear, however, how directly measured genetic risk is associated with aggressive behavior at different moments across adolescence and how genes might distinguish developmental trajectories of aggressive behavior. Here, a polygenic risk score derived from the EAGLE-Consortium genome-wide association study of aggressive behavior in children was tested as predictor of latent growth classes derived from those measures in an adolescent population (n = 2229, of which n = 1246 with genetic information) and a high-risk sample (n = 543, of which n = 335 with genetic information). In the population sample, the polygenic risk score explained variation in parent-reported aggressive behavior at all ages and distinguished between stable low aggressive behavior and moderate and high-decreasing trajectories based on parent-report. In contrast, the polygenic risk score was not associated with self-and teacher-reported aggressive behavior, and no associations were found in the high-risk sample. This pattern of results suggests that methodological choices made in genome-wide association studies impact the predictive power of polygenic risk scores, not just with respect to power but likely also in terms of generalizability and specificity.
Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course
Behavior Genetics
We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from The Netherlands (N = 13,471) and Australia (N = 5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12–70 years, Australia: 16–73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a ‘rolling weights’ model. In The Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41–70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role l...
Molecular Psychiatry
Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly 3 associated with the trait have not been identified. The present study by the Broad Antisocial Behavior 3 Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five 3 independent replication samples (N = 8,058) with genotypic data and broad measures of ASB. We 3 identified the first significant genetic associations with broad ASB, involving common intronic 3 variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, P = 6.32 x 10-10). 3 Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing 3 a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). The 3 SNP-based heritability of ASB was 8.4% (s.e.= 1.2%). Polygenic-risk-score (PRS) analyses in 3 independent samples revealed that the genetic risk for ASB was associated with several antisocial 4 outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, 4
Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior
JAMA psychiatry, 2017
Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derive...
Gene set enrichment analysis to create polygenic scores: a developmental examination of aggression
Translational Psychiatry
Previous approaches for creating polygenic risk scores (PRSs) do not explicitly consider the biological or developmental relevance of the genetic variants selected for inclusion. We applied gene set enrichment analysis to meta-GWAS data to create developmentally targeted, functionally informed PRSs. Using two developmentally matched meta-GWAS discovery samples, separate PRSs were formed, then examined in time-varying effect models of aggression in a second, longitudinal sample of children (n = 515, 49% female) in early childhood (2-5 years old), and middle childhood (7.5-10.5 years old). Functional PRSs were associated with aggression in both the early and middle childhood models.
Journal of Child Psychology and Psychiatry, 2020
BackgroundAggression 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.MethodsIndividual 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 sam...
Twin Research, 1999
Previous behaviour genetic studies of aggression have yielded inconsistent results: reported heritabilities for different types of aggressive behaviour ranging from 0 to 0.98. In the present study, 247 adult twin pairs (183 MZ pairs; 64 same-sex DZ pairs) were administered seven selfreport questionnaires which yielded 18 measures of aggression. Univariate genetic analyses showed moderate to high heritabilities for 14 of these 18 measures and for a general aggression factor and three correlated aggression factors extracted from the measures. Multivariate genetic analyses showed sizeable genetic correlations between the different dimensions of aggression. Thus, individual differences in many types of aggressive behaviour are attributable to some extent to genetic factors and there is considerable overlap between the genes that operate on different types of aggressive behaviour.
Behavior genetics of aggression in children: Review and future directions
Developmental Review, 2002
A thorough understanding of factors that influence aggression in children cannot be achieved without including behavior genetic studies that allow us to examine the effects of shared versus non-shared environment, as well as genes, on aggressive behaviors. This review details the growing body of evidence on the genetic effects on aggression. The majority of twin and adoption studies on antisocial behavior in children suggest that genetic effects are important influences, but most of these studies utilize parent reports rather than observational data. Some recent studies of nonparent raters are beginning to suggest that aggression in childhood may indeed be heritable and that this may not be a function simply of parent reporting bias. Future studies will need to focus on gene-environment correlations and interactions to begin to disentangle the myriad ways that children and the people in their environments inter-relate and mutually affect each other.