The female protective effect against autism spectrum disorder

Emilie M. Wigdor; Daniel J. Weiner; Jakob Grove; Jack M. Fu; Wesley Kurt Thompson; Caitlin E. Carey; Nikolas A. Baya; Celia van der Merwe; Raymond Kenney Walters; F. Kyle Satterstrom; Duncan S. Palmer; Anders Rosengren; Jonas Bybjerg‐Grauholm; DAVID MICHAEL HOUGAARD; Preben Bo Mortensen; Mark J. Daly; Michael E. Talkowski; Stephan Sanders; Somer L. Bishop; Anders Dupont Børglum; Elise Robinson

doi:10.1016/j.xgen.2022.100134

Genetic & Genomic MedicineCell GenomicsJun 1, 2022

Peer-reviewed journal article

The female protective effect against autism spectrum disorder

Emilie M. Wigdor iD, Daniel J. Weiner iD, Jakob Grove iD, Jack M. Fu iD, Wesley Kurt Thompson iD, Caitlin E. Carey iD, Nikolas A. Baya iD, Celia van der Merwe iD, Raymond Kenney Walters iD, F. Kyle Satterstrom iD, Duncan S. Palmer iD, Anders Rosengren iD, Jonas Bybjerg‐Grauholm iD, DAVID MICHAEL HOUGAARD iD, Preben Bo Mortensen iD, Mark J. Daly iD, Michael E. Talkowski iD, Stephan Sanders iD, Somer L. Bishop iD, Anders Dupont Børglum iD, Elise Robinson iD

Abstract

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.

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