Child Polygenic Risk for Psychiatric Disorders Does Not Explain the Association Between Antenatal Maternal Symptoms of Depression and Child Mental Health

Background: There is considerable evidence for an association between antenatal maternal symptoms of depression and anxiety and an increased risk for child mental health problems. One possible major factor that has not been given significant attention is the genomic risk for psychiatric disorders, which may confound (e.g., vertical transmission of genetic risk factors from mother to child) or modify the impact of prenatal exposures on symptom development. Using recent advances in polygenic risk scores, we tested the hypothesis that child genomic risk is a confounder or effect modifier of antenatal maternal symptoms of depression or anxiety on child psychopathology. Methods: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a large prospective cohort from the United Kingdom with measures of antenatal maternal mood and child mental health data from 4–16 years. We quantified child genomic risk for ADHD, schizophrenia, and depression using established polygenic risk scores. Outcomes were internalising, externalising, and total emotional/behavioural difficulties from childhood to mid-adolescence. We analysed the data longitudinally with generalized estimating equations (n=5,237) with secondary analyses in an independent prospective cohort of children from the Finnish PREDO study (n=514). Findings: Maternal mood and child genomic risk additively predicted mental health symptoms across childhood and into mid-adolescence. There was a robust prediction of child and adolescent mental health from both antenatal maternal depression (Estimate=0·024, 95% CI: 0·019–0·029, p<0·001) and anxiety (Est.=0·029, CI: 0·022–0·036, p<0·001) independent of multiple measures of child genomic risk for mental disorders with a similar independent effect of maternal depression (B=0·156, CI: 0·067–0·244, p=0·001) on child symptoms in an independent cohort. Interpretation: These findings provide the most direct test to date of the genomic contribution to the in utero origins of mental health hypothesis. Results indicate a modest influence of PRS on the emergence of symptoms from early childhood through adolescence. The findings also further evidence that antenatal maternal distress independently constitutes a distinct risk for child psychiatric symptoms into adolescence. Funding Statement: UK Medical Research Council, CIFAR Child and Brain Development Program, Canada First Research Excellence Fund: Healthy Brains for Healthy Lives initiative at McGill University, the JPB Foundation through a grant to the JPB Research Network on Toxic Stress: A Project of the Center on the Developing Child at Harvard University, Jacobs Foundation, Fonds de recherche du Quebec-Sante, Brain and Behavior Research Foundation, Pfeil Foundation and National Institutes of Health (R01 MH073842 and UG3/UH3 OD023349), Academy of Finland. Declaration of Interests: None to declare. Ethics Approval Statement: Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees.