The Contribution of Common and Rare Genetic Variation to Emotional and Behavioural Symptoms in Childhood and Adolescence

Genetic factors influence vulnerability to common mental health conditions, but their role in early-life mental health remains understudied. We analysed genotype array and exome sequence data from two birth cohorts (Millenium Cohort Study and Avon Longitudinal Study of Parents and Children; n=5,320-8,622) to assess common and rare variant contributions to internalising and externalising symptoms across development. For both symptom domains, we identified associations with several polygenic indices (PGIs) that generally remained stable across development. For externalising symptoms, many of these associations reflected direct genetic effects. Concordant results were observed in the Born in Bradford cohort. A higher exome-wide burden of deleterious rare variants was associated with increased externalising (p-adj<0.03) and internalising symptoms (p-adj<0.01); trio models indicated direct genetic effects on externalising in MCS (p<0.05; p-adj>0.05) and on internalising symptoms in ALSPAC (p-adj<0.02). Common and rare genetic variants contributed independently, jointly explaining 2% of the variance in internalising and 5-7% in externalising symptoms. Finally, we show that the direct genetic effects of several PGIs and of deleterious rare variants on adolescent mental health are mediated by childhood externalising behaviours and/or cognitive ability. This study provides new insights into the genetic architecture of early-life mental health and identifies promising avenues for future research.