Common and rare genetic variant associations with cognitive performance across development in British birth cohorts

Abstract Genetic variants that correlate with adult cognitive performance are also associated with rare neurodevelopmental conditions involving cognitive deficits in children. However, their association with cognition across early life remains poorly understood. Using 6,495 children from the Avon Longitudinal Study of Parents and Children, we show that, as children age, the association between cognitive ability and polygenic indices for educational attainment and its cognitive component increases (PGI EA × age interaction per 10 years: 0.033 [0.020, 0.047], PGI Cog × age: 0.0232 [0.0096, 0.0367]). Conversely, negative associations with deleterious rare variant burden attenuate with age (RVB pLoF × age: 0.0239 [0.0110, 0.0368]). Using trio analyses, we show that these age-related trends are consistent with contributions from direct genetic effects. We find that the increasing associations with polygenic indices are stronger in individuals at the upper end of the phenotype distribution, whereas the attenuating associations with rare variant burden are stronger in those at the lower end. Our findings may help explain the apparent incomplete penetrance of rare damaging variants associated with neurodevelopmental conditions.