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Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

ABSTRACT: Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10^-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression r_g = 0.63, insomnia r_g = 0.47), physical health (overweight r_g = 0.19, waist-to-hip ratio r_g = 0.32), smoking (r_g = 0.54), cognitive ability (intelligence r_g = -0.40), educational attainment (years of schooling r_g = -0.46) and reproductive traits (age at first birth r_g = -0.58, father's age at death r_g = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

SUBMITTER: Tielbeek JJ

PROVIDER: S-EPMC10902879 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Tielbeek Jorim J JJ Uffelmann Emil E Williams Benjamin S BS Colodro-Conde Lucía L Gagnon Éloi É Mallard Travis T TT Levitt Brandt E BE Jansen Philip R PR Johansson Ada A Sallis Hannah M HM Pistis Giorgio G Saunders Gretchen R B GRB Allegrini Andrea G AG Rimfeld Kaili K Konte Bettina B Klein Marieke M Hartmann Annette M AM Salvatore Jessica E JE Nolte Ilja M IM Demontis Ditte D Malmberg Anni L K ALK Burt S Alexandra SA Savage Jeanne E JE Sugden Karen K Poulton Richie R Harris Kathleen Mullan KM Vrieze Scott S McGue Matt M Iacono William G WG Mota Nina Roth NR Mill Jonathan J Viana Joana F JF Mitchell Brittany L BL Morosoli Jose J JJ Andlauer Till F M TFM Ouellet-Morin Isabelle I Tremblay Richard E RE Côté Sylvana M SM Gouin Jean-Philippe JP Brendgen Mara R MR Dionne Ginette G Vitaro Frank F Lupton Michelle K MK Martin Nicholas G NG Castelao Enrique E Räikkönen Katri K Eriksson Johan G JG Lahti Jari J Hartman Catharina A CA Oldehinkel Albertine J AJ Snieder Harold H Liu Hexuan H Preisig Martin M Whipp Alyce A Vuoksimaa Eero E Lu Yi Y Jern Patrick P Rujescu Dan D Giegling Ina I Palviainen Teemu T Kaprio Jaakko J Harden Kathryn Paige KP Munafò Marcus R MR Morneau-Vaillancourt Geneviève G Plomin Robert R Viding Essi E Boutwell Brian B BB Aliev Fazil F Dick Danielle M DM Popma Arne A Faraone Stephen V SV Børglum Anders D AD Medland Sarah E SE Franke Barbara B Boivin Michel M Pingault Jean-Baptiste JB Glennon Jeffrey C JC Barnes J C JC Fisher Simon E SE Moffitt Terrie E TE Caspi Avshalom A Polderman Tinca J C TJC Posthuma Danielle D

Molecular psychiatry 20221025 11

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the f ...[more]

PMID: 36284158

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Project description:ImportanceAntisocial 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.ObjectivesTo 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.Design, setting, and participantsGenome-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).Main outcome and measuresThis study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges.ResultsThe discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected.Conclusions and relevanceThe Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.

Project description:Aluminum (Al) toxicity is a primary limitation to crop productivity on acid soils, and rice has been demonstrated to be significantly more Al tolerant than other cereal crops. However, the mechanisms of rice Al tolerance are largely unknown, and no genes underlying natural variation have been reported. We screened 383 diverse rice accessions, conducted a genome-wide association (GWA) study, and conducted QTL mapping in two bi-parental populations using three estimates of Al tolerance based on root growth. Subpopulation structure explained 57% of the phenotypic variation, and the mean Al tolerance in Japonica was twice that of Indica. Forty-eight regions associated with Al tolerance were identified by GWA analysis, most of which were subpopulation-specific. Four of these regions co-localized with a priori candidate genes, and two highly significant regions co-localized with previously identified QTLs. Three regions corresponding to induced Al-sensitive rice mutants (ART1, STAR2, Nrat1) were identified through bi-parental QTL mapping or GWA to be involved in natural variation for Al tolerance. Haplotype analysis around the Nrat1 gene identified susceptible and tolerant haplotypes explaining 40% of the Al tolerance variation within the aus subpopulation, and sequence analysis of Nrat1 identified a trio of non-synonymous mutations predictive of Al sensitivity in our diversity panel. GWA analysis discovered more phenotype-genotype associations and provided higher resolution, but QTL mapping identified critical rare and/or subpopulation-specific alleles not detected by GWA analysis. Mapping using Indica/Japonica populations identified QTLs associated with transgressive variation where alleles from a susceptible aus or indica parent enhanced Al tolerance in a tolerant Japonica background. This work supports the hypothesis that selectively introgressing alleles across subpopulations is an efficient approach for trait enhancement in plant breeding programs and demonstrates the fundamental importance of subpopulation in interpreting and manipulating the genetics of complex traits in rice.

Project description:We investigated gene-environment (G × E) interactions related to childhood antisocial behavior between polymorphisms implicated by recent genome-wide association studies (GWASs) and two key environmental adversities (maltreatment and smoking during pregnancy) in a large population cohort (ALSPAC). We also studied the MAOA candidate gene and addressed comorbid attention-deficit/hyperactivity disorder (ADHD). ALSPAC is a large, prospective, ethnically homogeneous British cohort. Our outcome consisted of mother-rated conduct disorder symptom scores at age 7;9 years. G × E interactions were tested in a sex-stratified way (α = 0.0031) for four GWAS-implicated variants (for males, rs4714329 and rs9471290; for females, rs2764450 and rs11215217), and a length polymorphism near the MAOA-promoter region. We found that males with rs4714329-GG (P = 0.0015) and rs9471290-AA (P = 0.0001) genotypes were significantly more susceptible to effects of smoking during pregnancy in relation to childhood antisocial behavior. Females with the rs11215217-TC genotype (P = 0.0018) were significantly less susceptible to effects of maltreatment, whereas females with the MAOA-HL genotype (P = 0.0002) were more susceptible to maltreatment effects related to antisocial behavior. After adjustment for comorbid ADHD symptomatology, aforementioned G × E's remained significant, except for rs11215217 × maltreatment, which retained only nominal significance. Genetic variants implicated by recent GWASs of antisocial behavior moderated associations of smoking during pregnancy and maltreatment with childhood antisocial behavior in the general population. While we also found a G × E interaction between the candidate gene MAOA and maltreatment, we were mostly unable to replicate the previous results regarding MAOA-G × E's. Future studies should, in addition to genome-wide implicated variants, consider polygenic and/or multimarker analyses and take into account potential sex stratification.

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Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

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Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

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