Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach

Abstract

Background: Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene-environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, we aimed to delineate the sources of gene-environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health.

Methods: We did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank (n=143 473), Psychiatric Genomics Consortium (n=26 290), Avon Longitudinal Study of Parents and Children (n=8346), Adolescent Brain Cognitive Development Study (n=5400), and Generation R (n=1905). We included individuals who had phenotypic and genetic data available. We investigated single nucleotide polymorphism heritability and genetic correlations among different subtypes, operationalisations, and reports of childhood maltreatment. Family-based and population-based polygenic score analyses were done to elucidate gene-environment correlation mechanisms. We used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions.

Findings: Our meta-analysis of genome-wide association studies (N=185 414) identified 14 independent loci associated with childhood maltreatment (13 novel). We identified high genetic overlap (genetic correlations 0·24-1·00) among different maltreatment operationalisations, subtypes, and reporting methods. Within-family analyses provided some support for active and reactive gene-environment correlation but did not show the absence of passive gene-environment correlation. Robust Mendelian randomisation suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein concentration).

Interpretation: Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment. Family-based analyses point to a role of active and reactive gene-environment correlation, with equivocal support for passive correlation. Mendelian randomisation supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. Our study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects.

Funding: Wellcome Trust, UK Medical Research Council, Horizon 2020, National Institute of Mental Health, and National Institute for Health Research Biomedical Research Centre.

Figure 1

Study profile PGC=Psychiatric Genomics Consortium. ALSPAC=Avon Longitudinal Study of Parents and Children. SNP=single nucleotide polymorphism. GWAS=genome-wide association study. pTDT=polygenic transmission disequilibrium test. SSC=Simons Simplex Collection.

Figure 2

SNP heritability and genetic correlations between phenotypic operationalisations and subtypes of childhood maltreatment (A) SNP heritability of the four phenotypic definitions of childhood maltreatment and 95% CIs (n=19 559). (B) Genetic correlations between the four phenotypic operationalisations of childhood maltreatment (n=19 559). (C) SNP heritability of the subtypes of childhood maltreatment (binarised) alongside the log-transformed sum-score of childhood maltreatment and 95% CIs (n=19 559). (D) Genetic correlations between subtypes of childhood maltreatment and log-transformed sum-score of childhood maltreatment (n=19 559). SNP=single nucleotide polymorphism.

Figure 3

Circular Manhattan plot of childhood maltreatment Circular Manhattan plot for the GWAS meta-analysis of prospectively and retrospectively reported childhood maltreatment (n=185 414, outer ring), and retrospectively reported childhood maltreatment (n=169 766, inner ring). Red lines indicate GWAS significance threshold (p=5 × 10^–8). The vertical axis provides the p values for single nucleotide polymorphisms included in the GWAS meta-analyses. GWAS=genome-wide association study.

Figure 4

Delineating different gene–environment correlation mechanisms (A) Regression estimates and 95% CIs of active and reactive, passive, and total effects of childhood maltreatment PGS on childhood maltreatment (n=12 855 included 2849 sibling pairs). (B) Polygenic transmission disequilibrium test to investigate over-transmission of childhood maltreatment polygenic scores from parents to autistic children and non-autistic siblings in two cohorts: SSC (n=2234 autistic individuals and 1829 non-autistic siblings) and SPARK (n=2957 autistic individuals and 1567 non-autistic siblings). Mean PGS over-transmission (difference between standardised parental mean PGS and standardised child mean PGS) and 95% CIs provided. (C) Effect of childhood maltreatment PGS on prospectively measured childhood maltreatment (age 0–17 years) in Avon Longitudinal Study of Parents and Children (unadjusted model). The models were adjusted for parental alcohol consumption, parental depression, parental experience of childhood maltreatment, and parental smoking, all measured at the time of pregnancy. Odds ratios and 95% CIs are provided. Sample sizes are provided in the appendix (pp 71–72). PGS=polygenic scores. SSC=Simons Simplex Collection.

Figure 5

Mendelian randomisation analyses Scatter plots of the SNP effects of childhood maltreatment on major depressive disorder (A), schizophrenia (B), and ADHD (C). Scatter plots of the SNP effects of major depressive disorder (D), schizophrenia (E), and ADHD (F) on childhood maltreatment. All units of associations are log-odds ratios. Slopes provided correspond to three different Mendelian randomisation methods used (inverse variance-weighted, weighted median, and Mendelian randomisation-Egger). The Mendelian randomisation-Egger intercept was significant only for the causal effect of childhood maltreatment on schizophrenia (B; p=0·012). SNP=single nucleotide polymorphism.