Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Dec 2023
06 Dec 2023
Historique:
received:
29
09
2022
accepted:
18
11
2023
medline:
11
12
2023
pubmed:
7
12
2023
entrez:
6
12
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38057346
doi: 10.1038/s41467-023-43776-0
pii: 10.1038/s41467-023-43776-0
pmc: PMC10700338
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8077Subventions
Organisme : NIMH NIH HHS
ID : R01 MH115993
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105746
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115958
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115961
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115959
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115960
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115962
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH115963
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Investigateurs
Yana Bromberg
(Y)
Lawrence W Brown
(LW)
Xiaolong Cao
(X)
Keun-Ah Cheon
(KA)
Kyungun Cheong
(K)
Hannyung Choi
(H)
Barbara J Coffey
(BJ)
Li Deng
(L)
Carolin Fremer
(C)
Blanca Garcia-Delgar
(B)
Donald L Gilbert
(DL)
Danea Glover
(D)
Dorothy E Grice
(DE)
Julie Hagstrøm
(J)
Tammy Hedderly
(T)
Isobel Heyman
(I)
Hyun Ju Hong
(HJ)
Chaim Huyser
(C)
Heejoo Kim
(H)
Young Key Kim
(YK)
Eunjoo Kim
(E)
Young-Shin Kim
(YS)
Robert A King
(RA)
Yun-Joo Koh
(YJ)
Sodahm Kook
(S)
Samuel Kuperman
(S)
Junghan Lee
(J)
Bennett L Leventhal
(BL)
Marcos Madruga-Garrido
(M)
Dararat Mingbunjerdsuk
(D)
Pablo Mir
(P)
Astrid Morer
(A)
Tara L Murphy
(TL)
Kirsten Müller-Vahl
(K)
Alexander Münchau
(A)
Cara Nasello
(C)
Dong Hun Oh
(DH)
Kerstin J Plessen
(KJ)
Veit Roessner
(V)
Eun-Young Shin
(EY)
Dong-Ho Song
(DH)
Jungeun Song
(J)
Joshua K Thackray
(JK)
Frank Visscher
(F)
Samuel H Zinner
(SH)
Informations de copyright
© 2023. The Author(s).
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