The female protective effect against autism spectrum disorder

Autism spectrum disorder (ASD) is diagnosed 3-4 times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common, inherited genetic risk for ASD are less studied. Leveraging the nationally representative Danish iPSYCH resource, we found siblings of female ASD cases had higher rates of ASD than siblings of male ASD cases (P < 0.01). In the Simons Simplex and SPARK collections, mothers of ASD cases carried more polygenic risk for ASD than fathers of ASD cases (P = 7.0 10-7). Male unaffected siblings under-inherited polygenic risk (P = 0.03); female unaffected siblings did not. Further, female ASD cases without a high-impact de novo variant over-inherited nearly three-fold the polygenic risk of male cases with a high-impact de novo (P = 0.02). Our findings support a FPE against ASD that includes common, inherited genetic variation.