Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

Authors

• Alden Y. Huang, University of California
• Dongmei Yu, Massachusetts General Hospital, Broad Institute of MIT and Harvard
• Lea K. Davis, Vanderbilt University Medical Center
• Jae Hoon Sul, University of California
• Fotis Tsetsos, Purdue University
• Vasily Ramensky, University of California, Moscow Institute of Physics and Technology
• Ivette Zelaya, University of California
• Eliana Marisa Ramos, University of California
• Lisa Osiecki, Massachusetts General Hospital
• Jason A. Chen, University of California
• Lauren M. McGrath, University of DenverFollow
• Cornelia Illmann, Massachusetts General Hospital
• Paul Sandor, University of Toronto
• Cathy L. Barr, Krembil Research Institute
• Marco Grados, Johns Hopkins University School of Medicine
• Harvey S. Singer, Johns Hopkins University School of Medicine
• Markus M. Nöthen, University of Bonn
• Johannes Hebebrand, University Hospital Essen, University of Duisburg-Essen
• Robert A. King, Yale University School of Medicine
• Yves Dion, University of Montréal
• Guy Rouleau, McGill University
• Cathy L. Budman, Hofstra Northwell School of Medicine
• Christel Depienne, Université de Strasbourg, Brain and Spine Institute
• Yulia Worbe, Brain and Spine Institute
• Andreas Hartmann, Brain and Spine Institute
• Kirsten R. Müller-Vahl, Hannover Medical School
• Manfred Stuhrmann, Hannover Medical School
• Harald Aschauer, Medical University Vienna
• Mara Stamenkovic, Medical University Vienna
• Monika Schloegelhofer, Medical University Vienna
• Anastasios Konstantinidis, Medical University Vienna, Center for Mental Health Muldenstrasse
• Gholson J. Lyon, Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory
• William M. McMahon, University of Utah
• Csaba Barta, Semmelweis University
• Zsanett Tarnok, Vadaskert Child and Adolescent Psychiatric Hospital
• Peter Nagy, Vadaskert Child and Adolescent Psychiatric Hospital
• James R. Batterson, Children’s Mercy Hospital
• Renata Rizzo, Università di Catania
• Danielle C. Cath, University Medical Center Groningen & Drenthe Mental Health Center
• Tomasz Wolanczyk, Medical University of Warsaw
• Cheston Berlin, Penn State University College of Medicine
• Irene A. Malaty, University of Florida
• Michael S. Okun, University of Florida
• Douglas W. Woods, Marquette University, University of Wisconsin-Milwaukee
• Elliott Rees, Cardiff University
• Carlos N. Pato, SUNY Downstate Medical Center
• Michele T. Pato, SUNY Downstate Medical Center
• James A. Knowles, University of Southern California
• Danielle Posthuma, VU University Amsterdam
• David L. Pauls, Massachusetts General Hospital
• Nancy J. Cox, Vanderbilt University Medical Center
• Benjamin M. Neale, Massachusetts General Hospital
• Nelson B. Freimer, University of California
• Peristera Paschou, Purdue University
• Carol A. Mathews, University of Florida
• Jeremiah M. Scharf, Massachusetts General Hospital, Broad Institute of MIT and Harvard
• Giovanni Coppola, University of California
• Ruth D. Bruun, The Tourette Syndrome Association International Consortium for Genetics
• Sylvain Chouinard, The Tourette Syndrome Association International Consortium for Genetics
• Sabrina Darrow, The Tourette Syndrome Association International Consortium for Genetics
• Erica Greenberg, The Tourette Syndrome Association International Consortium for Genetics
• Matthew E. Hirschtritt, The Tourette Syndrome Association International Consortium for Genetics
• Roger Kurlan, The Gilles de la Tourette Syndrome GWAS Replication Initiative
• James F. Leckman, The Gilles de la Tourette Syndrome GWAS Replication Initiative
• Mary M. Robertson, The Gilles de la Tourette Syndrome GWAS Replication Initiative
• Jan Smit, The Gilles de la Tourette Syndrome GWAS Replication Initiative

Publication Date

6-21-2017

Document Type

Article

Organizational Units

College of Arts Humanities and Social Sciences, Psychology

Keywords

Tourette Syndrome, Tic disorders, Neurodevelopmental disorders, Genetics, Structural variation, Copy number variation, NRXN1, CNTN6

Abstract

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39–3.79], p = 1.2 × 10−3) and known, pathogenic CNVs (OR = 3.03 [1.85–5.07], p = 1.5 × 10−5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6–156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

Copyright Date

6-21-2017

Copyright Statement / License for Reuse

All Rights Reserved.

Rights Holder

Elsevier Inc.

Provenance

Received from CHORUS

Language

English (eng)

Publication Statement

Copyright is held by Elsevier Inc. User is responsible for all copyright compliance. This article was originally published as:

Huang, A. Y., Yu, D., Davis, L. K., Sul, J. H., Tsetsos, F., Ramensky, V., . . . Smit, J. (2017). Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette Syndrome. Neuron, 94(6), 1101-1111. https://doi.org/10.1016/j.neuron.2017.06.010

Publication Title

Neuron

Volume

94

Issue

6

First Page

1101

Last Page

1111

ISSN

1097-4199

PubMed ID

28641109

Recommended Citation

Huang, A. Y., Yu, D., Davis, L. K., Sul, J. H., Tsetsos, F., Ramensky, V., . . . Smit, J. (2017). Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette Syndrome. Neuron, 94(6), 1101-1111. https://doi.org/10.1016/j.neuron.2017.06.010

DOI Link

https://doi.org/10.1016/j.neuron.2017.06.010