24.6 EVALUATING THE GENOMIC CONTRIBUTION TO THE FETAL ORIGINS OF MENTAL HEALTH: A TEST USING POLYGENIC RISK SCORES

Abstract

The fetal origins hypothesis, which emphasizes adaptations to in utero exposures with long-term implications for brain and behavior, has emerged as a leading conceptual model for mental health research. One potentially major factor that has not been given significant attention in existing studies is child genomic risk for mental health disorders, which may confound or modify the association between prenatal exposures and child mental health. We capitalize on recent advances in population genetics, specifically polygenic risk scores, to test if child polygenic risk for major mental health disorders confounds or modifies the relationship between maternal antenatal depression and child psychopathology. The Avon Longitudinal Study of Parents and Children (ALSPAC) provided measures of maternal antenatal mood and child mental health data from 4 to 16 years of age. We used polygenic risk scores to derive measures of child genomic risk for ADHD, schizophrenia, and depression. Child outcomes included internalizing, externalizing, and total emotional/behavioral difficulties from childhood to midadolescence. Our primary analysis focuses on longitudinal symptom data from the ALSPAC cohort (n = 5237) with secondary analyses in an independent cohort of children from the PREDO (Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction) cohort (n = 514). There was a robust prediction of child and adolescent mental health from maternal antenatal depression, or maternal anxiety, independent of child polygenic risk for ADHD, schizophrenia, or depression; there were similar independent effects of maternal depression on child mental health in an independent cohort. These findings provide the most direct test to date of the genomic contribution to the fetal origins of mental health hypothesis and indicate a modest influence of polygenic risk scores on the emergence of symptoms from early childhood through adolescence. Our findings further underscore the potential value of investing in mental health supports in pregnancy for the benefit of both mother and child.