Abstract
Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10-4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10-9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.
Highlights
Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype
In line with our analyses of the conventional PRSs for ADHD (PRSADHD), we examined the interaction between maternal CES-Dpre and xPRS calculated at a range of thresholds ( p ≤ .01- p ≤ 1.00)
Child PRSADHD moderated the association between maternal CES-Dpre and Child Behavior Checklist (CBCL) total problem of variance in child internalizing symptoms (R2 = .18, F (4,182) = 9.97, p = 2.55 × 10−7; Figures 2 and Supplementary Appendix A Figure S3). This Best-Fit PRSADHD consisted of 59,683 independent single nucleotide polymorphisms (SNPs)
Summary
Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health. The effect of maternal antenatal depression on child mental health shows considerable inter-individual variation such that we currently lack the ability to identify the children at greatest risk (Plomin & Simpson, 2013), which precludes targeted intervention. These intervention programs far show modest effects on measures of child neurodevelopment (Goodman, Cullum, Dimidjian, River, & Kim, 2018)
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