Dissecting the contribution of common variants to risk of rare neurodevelopmental conditions

Although rare neurodevelopmental conditions have a large Mendelian component, common genetic variants also contribute to risk. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents, its interplay with rare variants, and whether parents polygenic background contributes to their childrens risk beyond the direct effect of variants transmitted to the child (i.e. via indirect genetic effects potentially mediated through the prenatal environment or genetic nurture). Here, we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained [~]10% of variance in overall risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model, while both genetically undiagnosed patients and diagnosed patients with affected parents had significantly more risk than controls. In a trio-based model, using a polygenic score for neurodevelopmental conditions, the transmitted but not the non-transmitted parental alleles were associated with risk, indicating a direct genetic effect. In contrast, we observed no direct genetic effect of polygenic scores for educational attainment and cognitive performance, but saw a significant correlation between the childs risk and non-transmitted alleles in the parents, potentially due to indirect genetic effects and/or parental assortment for these traits. Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. Our findings thus suggest that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.