Interplay between genome-wide implicated genetic variants and environmental factors related to childhood antisocial behavior in the UK ALSPAC cohort

Abstract

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.

Keywords: ALSPAC; Aggression; Antisocial behavior; Gene–environment interaction; Maltreatment; Smoking during pregnancy.

Fig. 1

Genetic principal component analysis. Scatterplots of the first two genetic principal components of ALSPAC merged with the 1000 Genomes phase 1 data set. a Clustering of superpopulations from different continents, whereas b shows clustering of populations within Europe. PC1 principal component (1), PC2 principal component (2), SD standard deviation, CEPH Centre d’Etude du Polymorphisme Humain

Fig. 2

Sex- and genotype-stratified effects of environmental adversities in relation to childhood antisocial behavior. Genotype-moderated effects of smoking during pregnancy in males (a) and maltreatment in females (b). IRR incidence rate ratio, MAOA monoamine oxidase A, LPR length polymorphic region, MAOA-L/H MAOA low-/high-activity allele, Error bars show 95% confidence intervals for the IRR. Gene–environment (G × E) interaction P values are shown on top