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

Alden Y Huang; Dongmei Yu; Lea K Davis; Jae Hoon Sul; Fotis Tsetsos; Vasily Ramensky; Ivette Zelaya; Eliana Marisa Ramos; Lisa Osiecki; Jason A Chen; Lauren M McGrath; Cornelia Illmann; Paul Sandor; Cathy L Barr; Marco Grados; Harvey S Singer; Markus M Nöthen; Johannes Hebebrand; Robert A King; Yves Dion; Guy Rouleau; Cathy L Budman; Christel Depienne; Yulia Worbe; Andreas Hartmann; Kirsten R Müller-Vahl; Manfred Stuhrmann; Harald Aschauer; Mara Stamenkovic; Monika Schloegelhofer; Anastasios Konstantinidis; Gholson J Lyon; William M McMahon; Csaba Barta; Zsanett Tarnok; Peter Nagy; James R Batterson; Renata Rizzo; Danielle C Cath; Tomasz Wolanczyk; Cheston Berlin; Irene A Malaty; Michael S Okun; Douglas W Woods; Elliott Rees; Carlos N Pato; Michele T Pato; James A Knowles; Danielle Posthuma; David L Pauls; Nancy J Cox; Benjamin M Neale; Nelson B Freimer; Peristera Paschou; Carol A Mathews; Jeremiah M Scharf; Giovanni Coppola; Tourette Syndrome Association International Consortium for Genetics (TSAICG); Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)

doi:10.1016/j.neuron.2017.06.010

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

Neuron. 2017 Jun 21;94(6):1101-1111.e7. doi: 10.1016/j.neuron.2017.06.010.

Authors

Alden Y Huang¹, Dongmei Yu², Lea K Davis³, Jae Hoon Sul⁴, Fotis Tsetsos⁵, Vasily Ramensky⁶, Ivette Zelaya¹, Eliana Marisa Ramos⁴, Lisa Osiecki⁷, Jason A Chen¹, Lauren M McGrath⁸, Cornelia Illmann⁷, Paul Sandor⁹, Cathy L Barr¹⁰, Marco Grados¹¹, Harvey S Singer¹¹, Markus M Nöthen¹², Johannes Hebebrand¹³, Robert A King¹⁴, Yves Dion¹⁵, Guy Rouleau¹⁶, Cathy L Budman¹⁷, Christel Depienne¹⁸, Yulia Worbe¹⁹, Andreas Hartmann¹⁹, Kirsten R Müller-Vahl²⁰, Manfred Stuhrmann²¹, Harald Aschauer²², Mara Stamenkovic²³, Monika Schloegelhofer²³, Anastasios Konstantinidis²⁴, Gholson J Lyon²⁵, William M McMahon²⁶, Csaba Barta²⁷, Zsanett Tarnok²⁸, Peter Nagy²⁸, James R Batterson²⁹, Renata Rizzo³⁰, Danielle C Cath³¹, Tomasz Wolanczyk³², Cheston Berlin³³, Irene A Malaty³⁴, Michael S Okun³⁴, Douglas W Woods³⁵, Elliott Rees³⁶, Carlos N Pato³⁷, Michele T Pato³⁷, James A Knowles³⁸, Danielle Posthuma³⁹, David L Pauls⁷, Nancy J Cox³, Benjamin M Neale⁴⁰, Nelson B Freimer⁴, Peristera Paschou⁵, Carol A Mathews⁴¹, Jeremiah M Scharf⁴², Giovanni Coppola⁴³; Tourette Syndrome Association International Consortium for Genetics (TSAICG); Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)

Collaborators

Ruth D Bruun, Sylvain Chouinard, Sabrina Darrow, Erica Greenberg, Matthew E Hirschtritt, Roger Kurlan, James F Leckman, Mary M Robertson, Jan Smit

Affiliations

¹ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
⁶ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Moscow Institute of Physics and Technology, Dolgoprudny, Institusky 9, Moscow 141701, Russian Federation.
⁷ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ Department of Psychology, University of Denver, Denver, CO 80210, USA.
⁹ Toronto Western Research Institute, University Health Network and Youthdale Treatment Centres, University of Toronto, Toronto, ON M5T 2S8, Canada.
¹⁰ Krembil Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
¹¹ Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹² Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany; Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
¹³ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
¹⁴ Yale Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁵ University of Montréal, Montréal, QC H3T 1J4, Canada.
¹⁶ Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
¹⁷ Hofstra Northwell School of Medicine, Hempstead, NY 11549, USA.
¹⁸ IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, 67404 Illkirch Cedex, France; Brain and Spine Institute, UPMC/INSERM UMR_S1127, 75013 Paris Cedex 05, France.
¹⁹ Brain and Spine Institute, UPMC/INSERM UMR_S1127, 75013 Paris Cedex 05, France.
²⁰ Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, 30625 Hannover, Germany.
²¹ Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
²² Department of Psychiatry and Psychotherapy, Medical University Vienna, 1090 Vienna, Austria; Biopsychosocial Corporation, 1090 Vienna, Austria.
²³ Department of Psychiatry and Psychotherapy, Medical University Vienna, 1090 Vienna, Austria.
²⁴ Department of Psychiatry and Psychotherapy, Medical University Vienna, 1090 Vienna, Austria; Center for Mental Health Muldenstrasse, BBRZMed, 4020 Linz, Austria.
²⁵ Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
²⁶ Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA.
²⁷ Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1085 Budapest, Hungary.
²⁸ Vadaskert Child and Adolescent Psychiatric Hospital, 1021 Budapest, Hungary.
²⁹ Children's Mercy Hospital, Kansas City, KS 64108, USA.
³⁰ Dipartimento di Medicina Clinica e Sperimentale, Università di Catania, 95131 Catania, Italy.
³¹ Department of Psychiatry, University Medical Center Groningen & Drenthe Mental Health Center, 9700 RB Groningen, the Netherlands; Department of Clinical Psychology, Utrecht University, 3584 CS Utrecht, the Netherlands.
³² Department of Child Psychiatry, Medical University of Warsaw, 00-001 Warsaw, Poland.
³³ Penn State University College of Medicine, Hershey, PA 17033, USA.
³⁴ Department of Neurology and Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL 32607, USA.
³⁵ Marquette University, Milwaukee, WI 53233, USA; University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
³⁶ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff CF24 4HQ, Wales, UK.
³⁷ SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
³⁸ Department of Psychiatry & Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
³⁹ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, 1081 HV Amsterdam, the Netherlands.
⁴⁰ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴¹ Department of Psychiatry, Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
⁴² Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: jscharf@partners.org.
⁴³ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: gcoppola@ucla.edu.

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.

Keywords: CNTN6; NRXN1; Tourette Syndrome; copy number variation; genetics; neurodevelopmental disorders; structural variation; tic disorders.

MeSH terms

Adolescent
Adult
Calcium-Binding Proteins
Case-Control Studies
Cell Adhesion Molecules, Neuronal / genetics*
Child
Contactins / genetics*
DNA Copy Number Variations*
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Nerve Tissue Proteins / genetics*
Neural Cell Adhesion Molecules
Odds Ratio
Tourette Syndrome / genetics*
White People / genetics
Young Adult

Substances

CNTN6 protein, human
Calcium-Binding Proteins
Cell Adhesion Molecules, Neuronal
Contactins
NRXN1 protein, human
Nerve Tissue Proteins
Neural Cell Adhesion Molecules

Abstract

MeSH terms

Substances

Grants and funding