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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Sheng Wang - , University of California at San Francisco (Autor:in)
  • Belinda Wang - , University of California at San Francisco (Autor:in)
  • Vanessa Drury - , University of California at San Francisco (Autor:in)
  • Sam Drake - , University of California at San Francisco (Autor:in)
  • Nawei Sun - , University of California at San Francisco (Autor:in)
  • Hasan Alkhairo - , University of California at San Francisco (Autor:in)
  • Juan Arbelaez - , University of California at San Francisco (Autor:in)
  • Clif Duhn - , University of California at San Francisco (Autor:in)
  • Tourette International Collaborative Genetics (TIC Genetics) - (Autor:in)
  • Klinik und Poliklinik für Kinder- und Jugendpsychiatrie
  • Rutgers - The State University of New Jersey, New Brunswick
  • University of Pennsylvania
  • Yonsei University
  • University of Miami
  • Medizinische Hochschule Hannover (MHH)
  • Universitat de Barcelona
  • Cincinnati Children's Hospital Medical Center
  • Icahn School of Medicine at Mount Sinai
  • Capital Region of Denmark
  • King's College London (KCL)
  • University College London
  • Hallym University
  • Amsterdam University Medical Centers (UMC)
  • Levvel
  • Korea Institute for Children’s Social Development and Rudolph Child Research Center
  • Yale University
  • University of Iowa
  • Hospital Universitario Virgen del Rocio
  • University of Washington
  • Universidad de Sevilla
  • CIBER - Centro de Investigación Biomédica en Red
  • August Pi i Sunyer Biomedical Research Institute
  • Universität zu Lübeck
  • Université de Lausanne
  • National Health Insurance Corporation Ilsan Hospital

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.

Details

OriginalspracheEnglisch
Aufsatznummer8077
Seitenumfang18
FachzeitschriftNature communications
Jahrgang2023
Ausgabenummer14
PublikationsstatusVeröffentlicht - 6 Dez. 2023
Peer-Review-StatusJa

Externe IDs

PubMed 38057346

Schlagworte

Schlagwörter

  • Autism Spectrum Disorder/genetics, Humans, Attention Deficit Disorder with Hyperactivity/genetics, Male, Female, Autistic Disorder/genetics, Neurodevelopmental Disorders, Tourette Syndrome/genetics