Title

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

Document Type

Article

Publication Date

6-21-2017

Organizational Units

College of Arts Humanities and Social Sciences, Psychology

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.

Compass Link

https://du-primo.hosted.exlibrisgroup.com/permalink/f/1jii0mc/TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5568251

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