Rare Maternally Inherited Coding Variants on Chromosome X Carry Predominantly Male Risk in Autism, Tourette Syndrome, and Attention-deficit/Hyperactivity Disorder

Abstract

Autism spectrum disorders (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 TS and ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

Competing Interest Statement

Donald L. Gilbert has received salary/travel/honoraria from the Tourette Association of America, the Child Neurology Society, U.S. National Vaccine Injury Compensation Program, Ecopipam Pharmaceuticals, EryDel Pharmaceuticals, Elsevier, and Wolters Kluwer. Kirsten Müller-Vahl has received financial or material research support from EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), DFG: GZ MU 1527/3-1 and GZ MU 1527/3-2, BMBF: 01KG1421, National Institute of Mental Health (NIMH), Tourette Gesellschaft Deutschland e.V., Else-Kröner-Fresenius-Stiftung, GW pharmaceuticals, Almirall Hermal GmbH, Abide Therapeutics, and Therapix Biosiences. She has received consultant's honoraria from Abide Therapeutics, Boehringer Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Grouth, Columbia Care, CTC Communications Corp., Demecan, Ethypharm GmbH, Eurox Deutschland GmbH, Global Praxis Group Limited, Lundbeck, MCI Germany, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, and Tilray. She is an advisory/scientific board member for Alexion, CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, Ethypharm GmbH, IMC Germany, Leafly Deutschland GmbH, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, von Mende Marketing GmbH, Wayland Group, and Zambon. She has received speaker's fees from Aphria Deutschland GmbH, Almirall, Camurus, Cogitando GmbH, Emalex, Eurox Deutschland GmbH, Ever pharma GmbH, Meinhardt Congress GmbH, PR Berater, Spectrum Therapeutics GmbH, Takeda GmbH, Tilray, and Wayland Group. She has received royalties from Deutsches Ärzteblatt, Der Neurologie und Psychiater, Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and Kohlhammer. She served as a guest editor for Frontiers in Neurology on the research topic "The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects", is an associate editor for "Cannabis and Cannabinoid Research" and an Editorial Board Member of "Medical Cannabis and Cannabinoids" und "MDPI-Reports" and a Scientific board member for "Zeitschrift für Allgemeinmedizin". Michael C. O'Donovan and Michael J Owen received Research Grant from Takeda Pharmaceuticals out of scope of present work.

Funding Statement

This study was supported by grants from the National Institute of Mental Health to A.J.W and M.W.S (R01MH115963), A.J.W (R01NS105746), G.A.H. and J.A.T. (R01MH115958), Alyssa Rosen (R01MH115960), Donald L. Gilbert (R01MH115962), Samuel Kuperman (R01MH115961), Samuel H. Zinner (R01MH115993), and Barbara J. Coffey (R01MH115959); from the Tourette Association of America to A.J.W. (Young Investigator Award); from the Human Genetics Institute of New Jersey to G.A.H. and J.A.T.; and the New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS) to G.A.H. and J.A.T. We are also grateful to the NJCTS for facilitating the inception and organization of the TIC Genetics study. This study was also supported by the Weill Institute for Neurosciences (Startup Funding to A.J.W.) and the Overlook International Foundation (to M.W.S. and A.J.W.). The ADHD study was funded by the Wellcome Trust (to A.T., M.C.O., M.J.O.) and also by the MRC (A.T., K.L.), Action Research (A.T., M.C.O., M.J.O.) with project support from Sharifah Agha, Nigel Williams, Peter Holmans, and the core lab team at the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University. We also thank the Tourette Association of America International Consortium for Genetics (TAAICG) and the Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE) for their ongoing collaboration and support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Human Research Protection Program Institutional Review Board (IRB) of University of California, San Francisco gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors

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