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; iPSYCH Consortium; David M Hougaard; Preben Bo Mortensen; Mark J Daly; Michael E Talkowski; Stephan J Sanders; Somer L Bishop; Anders D Børglum; Elise B Robinson

doi:10.1016/j.xgen.2022.100134

The female protective effect against autism spectrum disorder

Cell Genom. 2022 Jun 8;2(6):100134. doi: 10.1016/j.xgen.2022.100134.

Authors

Emilie M Wigdor^{1

2}, Daniel J Weiner^{1

3}, Jakob Grove^{4

5

6

7}, Jack M Fu^{1

8}, Wesley K Thompson⁹, Caitlin E Carey^{1

3}, Nikolas Baya^{1

3}, Celia van der Merwe^{1

3}, Raymond K Walters^{1

3}, F Kyle Satterstrom^{1

3}, Duncan S Palmer^{1

3}, Anders Rosengren^{7

10}, Jonas Bybjerg-Grauholm^{7

11}; iPSYCH Consortium; David M Hougaard^{7

11}, Preben Bo Mortensen^{4

10

12

13}, Mark J Daly^{1

3

14}, Michael E Talkowski^{1

8}, Stephan J Sanders¹⁵, Somer L Bishop¹⁵, Anders D Børglum^{4

5

10}, Elise B Robinson^{1

3

16}

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
³ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Center for Genomics and Personalized Medicine (CGPM), Aarhus University, 8000 Aarhus, Denmark.
⁵ Department of Biomedicine (Human Genetics) and iSEQ Center, Aarhus University, 8000 Aarhus, Denmark.
⁶ Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark.
⁷ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark.
⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Laureate Institute for Brain Research, Tulsa, OK 74136, USA.
¹⁰ Institute of Biological Psychiatry, MHC Sct Hans, Copenhagen University Hospital, 4000 Roskilde, Denmark.
¹¹ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, 2300 Copenhagen, Denmark.
¹² National Center for Register-Based Research, Aarhus University, 8210 Aarhus, Denmark.
¹³ Center for Integrated Register-based Research, Aarhus University, 8210 Aarhus, Denmark.
¹⁴ Finnish Institute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland.
¹⁵ Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Abstract

Autism spectrum disorder (ASD) is diagnosed three to four 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, particularly within families. Leveraging the Danish iPSYCH 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; epidemiology; female protective effect; genetics; genomics; polygenic scores; recurrent risk; sex differences.

Abstract

Grants and funding