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Rare X-linked variants carry predominantly male risk in Autism, Tourette Syndrome, and ADHD

Wang, Sheng, Wang, Belinda, Drury, Vanessa, Drake, Sam, Sun, Nawei, Alkhairo, Hasan, Arbelaez, Juan, Duhn, Clif, Tourette International Collaborative Genetics (TIC Genetics), Bal, Vanessa, Langley, Kate ORCID:, Martin, Joanna ORCID:, Hoekstra, Pieter, Dietrich, Andrea, Xing, Jinchuan, Heiman, Gary, Tischfield, Jay, Fernandez, Thomas, Owen, Michael ORCID:, O'Donovan, Michael ORCID:, Thapar, Anita ORCID:, State, Matthew and Willsey, Jeremy 2023. Rare X-linked variants carry predominantly male risk in Autism, Tourette Syndrome, and ADHD. Nature Communications 14 , 8077. 10.1038/s41467-023-43776-0

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 23 August 2023
Date of Acceptance: 18 November 2023
Last Modified: 07 Dec 2023 10:12

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