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, Yana Bromberg, Lawrence W. Brown, Xiaolong Cao, Keun Ah Cheon, Kyungun Cheong, Hannyung Choi, Barbara J. Coffey, Li Deng, Carolin Fremer, Blanca Garcia-Delgar, Donald L. Gilbert, Danea GloverDorothy E. Grice, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Hyun Ju Hong, Chaim Huyser, Heejoo Kim, Young Key Kim, Eunjoo Kim, Young Shin Kim, Robert A. King, Yun Joo Koh, Sodahm Kook, Samuel Kuperman, Junghan Lee, Bennett L. Leventhal, Marcos Madruga-Garrido, Dararat Mingbunjerdsuk, Pablo Mir, Astrid Morer, Tara L. Murphy, Kirsten Müller-Vahl, Alexander Münchau, Cara Nasello, Dong Hun Oh, Kerstin J. Plessen, Veit Roessner, Eun Young Shin, Dong Ho Song, Jungeun Song, Joshua K. Thackray, Frank Visscher, Samuel H. Zinner, 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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article number8077
JournalNature communications
Issue number1
StatePublished - Dec 2023

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


Dive into the research topics of 'Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD'. Together they form a unique fingerprint.

Cite this