Cell Genomics (Jun 2022)
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,
- David M. Hougaard,
- Preben Bo Mortensen,
- Mark J. Daly,
- Michael E. Talkowski,
- Stephan J. Sanders,
- Somer L. Bishop,
- Anders D. Børglum,
- Elise B. Robinson
Affiliations
- Emilie M. Wigdor
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
- Daniel J. Weiner
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Jakob Grove
- Center for Genomics and Personalized Medicine (CGPM), Aarhus University, 8000 Aarhus, Denmark; Department of Biomedicine (Human Genetics) and iSEQ Center, Aarhus University, 8000 Aarhus, Denmark; Bioinformatics Research Centre, Aarhus University, 8000 Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark
- Jack M. Fu
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Wesley K. Thompson
- Laureate Institute for Brain Research, Tulsa, OK 74136, USA
- Caitlin E. Carey
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Nikolas Baya
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Celia van der Merwe
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Raymond K. Walters
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- F. Kyle Satterstrom
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Duncan S. Palmer
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Anders Rosengren
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark; Institute of Biological Psychiatry, MHC Sct Hans, Copenhagen University Hospital, 4000 Roskilde, Denmark
- Jonas Bybjerg-Grauholm
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, 2300 Copenhagen, Denmark
- David M. Hougaard
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, 2300 Copenhagen, Denmark
- Preben Bo Mortensen
- Center for Genomics and Personalized Medicine (CGPM), Aarhus University, 8000 Aarhus, Denmark; Institute of Biological Psychiatry, MHC Sct Hans, Copenhagen University Hospital, 4000 Roskilde, Denmark; National Center for Register-Based Research, Aarhus University, 8210 Aarhus, Denmark; Center for Integrated Register-based Research, Aarhus University, 8210 Aarhus, Denmark
- Mark J. Daly
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Finnish Institute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland
- Michael E. Talkowski
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Stephan J. Sanders
- Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Somer L. Bishop
- Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Anders D. Børglum
- Center for Genomics and Personalized Medicine (CGPM), Aarhus University, 8000 Aarhus, Denmark; Department of Biomedicine (Human Genetics) and iSEQ Center, Aarhus University, 8000 Aarhus, Denmark; Institute of Biological Psychiatry, MHC Sct Hans, Copenhagen University Hospital, 4000 Roskilde, Denmark
- Elise B. Robinson
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Corresponding author
- Journal volume & issue
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Vol. 2,
no. 6
p. 100134
Abstract
Summary: 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.
