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. MethodsWe 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 geneenvironment 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. Familybased 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.

Stressful life events increase the risk of major depressive episodes: A population-based twin study

“…Indicated causal patterns of influence on depression risk has been found for a number of specific SLEs included in the current study as well, such as combat exposure (Koenen et al, 2003), assault , sexual abuse (Kendler et al, 2000;Nelson et al, 2002), and romantic problems and job loss (Kendler & Gardner, 2001). Evidence of a causal effect of maltreatment in childhood on risk of major depression was also found in a recent GWAS meta-analysis using Mendelian Randomisation (Warrier et al, 2021).…”

Genetic and early environmental predictors of adulthood self-reports of trauma

“…In accordance with this, evidence suggests that retrospective self-reports are partly under genetic influence 13,14 . Similarly, reporter characteristics including personality traits, psychopathology and cognitive biases have also been found to have a heritable component [15][16][17] .…”

“…Increased genetic liability for autistic traits may lead to difficulty with social interaction, which could evoke adverse reactions, such as neglect or abuse from others (evocative gene-environment correlation), or increase the likelihood of being in dangerous environments (active gene-environment correlation) 61 . Consistent with this explanation, another study found over-transmission of genetic risk for reporting childhood trauma from parents to autistic children but not to their non-autistic siblings 14 . This suggests that the increased genetic risk of reporting childhood maltreatment in individuals with ASD may be partly explained by increased active and evocative gene-environment correlation, rather than passive.…”

“…Similarly, genome-wide association studies of retrospective self-reported childhood trauma find there is overlap with the specific genetic variants associated with personality, cognitive, behavioural, anthropometric and psychopathological traits, and find substantial genetic correlations between these traits and self-reported childhood trauma 14,20 . For example, self-reported childhood trauma showed significant genetic correlations with neuroticism, years of schooling, smoking, body mass index (BMI), autism spectrum disorder (ASD) and major depression 14 . In addition to exploring genetic correlations, genome-wide association data can be used to create polygenic scores.…”

Maternal body mass index in pregnancy and mental disorders in adult offspring: a record linkage study in Aberdeen, Scotland

“…On the other hand, maternal exposure to childhood maltreatment may also have contributed: Exposure to childhood maltreatment is associated with obesity risk 11 , also in pregnant women 46 , and childhood maltreatment predicts increased psychopathology risk both within the same 47 and the next 48 , 49 generation. A Mendelian randomization study suggests the effects on mental health within the same generation may be causal 50 . It is here of note that a large proportion of the mothers in the older subsample of the current study were children during World War II.…”