Nature Communications (Dec 2023)

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,
  • Tourette International Collaborative Genetics (TIC Genetics),
  • 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,
  • A. Jeremy Willsey

DOI
https://doi.org/10.1038/s41467-023-43776-0
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 18

Abstract

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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.