“The Female Protective Effect against Autism Spectrum Disorder”, Emilie M. Wigdor, Daniel J. Weiner, Jakob Grove, Jack M. Fu, Wesley K. Thompson, Caitlin E. Carey, Nikolas Baya, Celia van der Merwe, Raymond K. Walters, F. Kyle Satterstrom, Duncan S. Palmer, Anders Rosengren, Jonas Bybjerg-Grauholm, iPSY C. H. Consortium, David Hougaard, Preben Bo Mortensen, Mark J. Daly, Michael E. Talkowski, Stephan J. Sanders, Somer L. Bishop, Anders Børglum, Elise B. Robinson2022-06-08 (rare mutations, autism)⁠:

• Evidence of female protective effect against ASD from common, inherited variation

• Evidence of FPE in both affected and unaffected members of ASD-impacted families

• Mothers of children with ASD carry more genetic risk for ASDs than fathers

Autism spectrum disorder (ASD) is diagnosed 3–4× 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, particularly within families.

Leveraging the Danish iPSYCH [population registry] resource, we found siblings of female ASD cases (n = 1,707) had higher rates of ASD than siblings of male ASD cases (n = 6,270; p < 1.0 × 10⁻¹⁰). In the Simons Simplex and SPARK collections, mothers of ASD cases (n = 7,436) carried more polygenic risk for ASD than fathers of ASD cases (n = 5,926; 0.08 polygenic risk score [PRS] SD; p = 7.0 × 10⁻⁷). Further, male unaffected siblings under-inherited polygenic risk (n = 1,519; p = 0.03).

Using both epidemiologic and genetic approaches, our findings strongly support an FPE against ASD’s common inherited influences.

[Keywords: ASD, autism, genetics, genomics, epidemiology, sex differences, female protective effect, polygenic scores, recurrent risk]