Journal article
Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD
Nature communications, Vol.14(1), 8077
12/06/2023
DOI: 10.1038/s41467-023-43776-0
PMCID: PMC10700338
PMID: 38057346
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.Here, the authors clarify the architecture of genetic risk on chromosome X in three male-biased psychiatric disorders. Leveraging this information they identify an exome-wide significant autism risk gene, MAGEC3, and provide a path forward for future gene discovery on this chromosome.
Details
- Title: Subtitle
- Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD
- Creators
- Sheng Wang - University of California, San FranciscoBelinda Wang - University of California, San FranciscoVanessa Drury - University of California, San FranciscoSam Drake - University of California, San FranciscoNawei Sun - University of California, San FranciscoHasan Alkhairo - University of California, San FranciscoJuan Arbelaez - University of California, San FranciscoClif Duhn - University of California, San FranciscoYana BrombergLawrence W BrownXiaolong CaoKeun-Ah CheonKyungun CheongHannyung ChoiBarbara J CoffeyLi Deng - University of California, San FranciscoCarolin FremerBlanca Garcia-DelgarDonald L GilbertDanea GloverDorothy E GriceJulie HagstrømTammy HedderlyIsobel HeymanHyun Ju HongChaim HuyserHeejoo KimYoung Key KimEunjoo KimYoung-Shin KimRobert A KingYun-Joo KohSodahm KookSamuel KupermanJunghan LeeBennett L LeventhalMarcos Madruga-GarridoDararat MingbunjerdsukPablo MirAstrid MorerTara L MurphyKirsten Müller-VahlAlexander MünchauCara NaselloDong Hun OhKerstin J PlessenVeit RoessnerEun-Young ShinDong-Ho SongJungeun SongJoshua K ThackrayFrank VisscherSamuel H ZinnerVanessa H Bal - Rutgers, The State University of New JerseyKate Langley - Cardiff UniversityJoanna Martin - Cardiff UniversityPieter J Hoekstra - University of GroningenAndrea Dietrich - University Medical Center GroningenJinchuan Xing - Rutgers, The State University of New JerseyGary A Heiman - Rutgers, The State University of New JerseyJay A Tischfield - Rutgers, The State University of New JerseyThomas V Fernandez - Yale UniversityMichael J Owen - Cardiff UniversityMichael C O’DonovanAnita Thapar - Cardiff UniversityMatthew W State - University of California, San FranciscoA. Jeremy Willsey - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.14(1), 8077
- DOI
- 10.1038/s41467-023-43776-0
- PMID
- 38057346
- PMCID
- PMC10700338
- NLM abbreviation
- Nat Commun
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group
- Grant note
- DOI: 10.13039/100000025, name: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health, award: R01MH115963; name: Tourette Association of America (Young Investigator Award) the Weill Institute for Neurosciences (Startup Funding) the Overlook International Foundation
- Language
- English
- Date published
- 12/06/2023
- Academic Unit
- Psychiatry; Sociology and Criminology; International Programs; Epidemiology; Emergency Medicine; Anesthesia; Public Policy Center (Archive); School of Planning and Public Affairs; Political Science
- Record Identifier
- 9984521372602771
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