Schizophrenia risk alleles and neurodevelopmental outcomes in childhood: a population-based cohort study

Background Schizophrenia typically onsets after puberty but is often preceded by observable childhood neurodevelopmental impairments. Whether these childhood antecedents index genetic liability is unknown. We used polygenic risk scores derived from a patient discovery sample as indicators of the genetic liability of schizophrenia. Our aim was to identify the early childhood manifestations of this liability in a UK population-based cohort. Methods The study sample was the Avon Longitudinal Study of Parents and Children, a prospective population-based cohort study of 14701 children. Data were primarily analysed with regression-based analyses. Polygenic risk scores were generated from a published Psychiatric Genomics Consortium genome-wide association study. Outcomes were childhood (age 4-9 years) dimensional measures in four developmental domains with 12 indicators: cognition and learning, social and communication, emotion and mood regulation, and behaviour (n=5100-6952). Findings At age 7-9 years, schizophrenia polygenic risk scores showed associations with lower performance intelligence quotient (beta -0.056, OR 1.13 [95% CI 1.04-1.23]), poorer social understanding (beta -0.032, OR 1.08 [1.00-1.17]), worse language intelligibility and fluency (beta -0.032, OR 1.10 [1.02-1.20]), more irritability (beta 0.032, OR 1.07 [1.01-1.14]), and more headstrong behaviour (beta 0.031, OR 1.08 [1.02-1.15]). The schizophrenia polygenic risk scores also predicted social and behavioural impairments as early as age 4 years. Interpretation Childhood cognitive, social, behavioural, and emotional impairments, implicated as antecedents to schizophrenia in high-risk, developmental studies, might represent early manifestations of genetic liability.