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 David Arbelaez, Clif Duhn, Tourette International Collaborative Genetics (TIC Genetics), Yana Bromberg, Lawrence W. Brown, Xiaolong Cao, Keun‐Ah Cheon, Kyungun Cheong, Hannyung Choi, Barbara Coffey, Li Deng, Carolin Fremer, Blanca García-Delgar, Donald L. Gilbert, Danea Glover, Dorothy E. Grice, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Hyun Ju Hong, Chaim Huyser, Hee Joo Kim, Young Key Kim, Eun Joo Kim, Young‐Shin Kim, Robert A. King, Yun‐Joo Koh, Sodahm Kook, Samuel Kuperman, Junghan Lee, Bennett Leventhal, Marcos Madruga-Garrido, Dararat Mingbunjerdsuk, Pablo Mir, Ástrid Morer, Tara Murphy, Kirsten Müller‐Vahl, Alexander Münchau, Cara Nasello, Dong Hoon Oh, Kerstin Jessica Plessen, Veit Roessner, Eun‐Young Shin, Dong‐Ho Song, Jungeun Song, Joshua K. Thackray, Frank Visscher, Samuel H. Zinner, Vanessa H. Bal, K. Langley, Joanna Martin, Pieter J. Hoekstra, Andrea Dietrich, Jinchuan Xing, Gary A. Heiman, Jay A. Tischfield, Thomas Fernandez, Michael J. Owen, Michael O‘Donovan, Anita Thapar, Matthew W. State, A. Jeremy Willsey
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.