Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD

Sheng Wang, Belinda Wang, Vanessa Drury, Sam Drake, Nawei Sun, Hasan Alkhairo, Juan Arbelaez, Clif Duhn, Vanessa H. Bal, Kate Langley, Joanna Martin, Pieter J. Hoekstra, Andrea Dietrich, Jinchuan Xing, Gary A. Heiman, Jay A. Tischfield, Thomas V. Fernandez, Michael J. Owen, Michael C. O’Donovan, Anita Thapar, Matthew W. State and A. Jeremy Willsey ()
Additional contact information
Sheng Wang: University of California, San Francisco
Belinda Wang: University of California, San Francisco
Vanessa Drury: University of California, San Francisco
Sam Drake: University of California, San Francisco
Nawei Sun: University of California, San Francisco
Hasan Alkhairo: University of California, San Francisco
Juan Arbelaez: University of California, San Francisco
Clif Duhn: University of California, San Francisco
Vanessa H. Bal: Rutgers University
Kate Langley: Cardiff University School of Medicine
Joanna Martin: Cardiff University School of Medicine
Pieter J. Hoekstra: University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry
Andrea Dietrich: University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry
Jinchuan Xing: the State University of New Jersey
Gary A. Heiman: the State University of New Jersey
Jay A. Tischfield: the State University of New Jersey
Thomas V. Fernandez: Yale University School of Medicine
Michael J. Owen: Cardiff University School of Medicine
Michael C. O’Donovan: Cardiff University School of Medicine
Anita Thapar: Cardiff University School of Medicine
Matthew W. State: University of California, San Francisco
A. Jeremy Willsey: University of California, San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of “male vulnerability”, rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of “idiopathic” ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

Date: 2023
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DOI: 10.1038/s41467-023-43776-0

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