. 2017 Jun 21;94(6):1101-1111.e7.

doi: 10.1016/j.neuron.2017.06.010.

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

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, Affiliations

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.

PMID: 28641109
PMCID: PMC5568251
DOI: 10.1016/j.neuron.2017.06.010

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

Alden Y Huang et al. Neuron. 2017.

. 2017 Jun 21;94(6):1101-1111.e7.

doi: 10.1016/j.neuron.2017.06.010.

Authors

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.

PMID: 28641109
PMCID: PMC5568251
DOI: 10.1016/j.neuron.2017.06.010

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.

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Figures

**Figure 1. Flow chart of experimental procedures and analyses**
CNVs were called from genome-wide SNP genotype data generated from 2,434 TS cases and 4,093 controls (grey). Data processing, CNV detection and quality control steps (blue) are described in the STAR Methods. An outline of the main analyses is presented in red. Figures or tables relevant to each outlined step are shown in parentheses.

**Figure 2. Rare CNV burden in 2,434 TS cases and 4,093 controls**
(A) The global burden of all rare (<1% frequency) CNVs > 30kb is shown for genic (top) and non-genic (bottom) CNVs and stratified by CNV type (all, loss (deletions), gain (duplications)). Global CNV burden is compared using three different metrics: CNV count, total number of CNVs per subject; CNV length, aggregate length of all CNVs (in Mb); and CNV gene count, number of genes spanned by CNVs. Control rate, averaged baseline burden metric per control subject. Red boxes, odds ratios (box size is proportional to standard error); Blue lines indicate 95% confidence intervals. Genic CNVs are defined as those that overlap any exon of a known protein-coding gene (see STAR Methods). (B) Analyses in (A) were assessed further by partitioning CNV length burden of all CNVs (deletions + duplications) into different CNV size categories. Whiskers represent 95% confidence intervals. (C) The analysis in (B) was repeated for CNVs binned by frequency. Odds ratios (OR) were calculated from logistic regression adjusted for covariates using standardized burden metrics (STAR Methods). ORs >1 indicate an increased TS risk.

**Figure 3. Large, singleton CNVs and known pathogenic variants are overrepresented in TS**
(A) CNV count burden restricted to genic singleton events, stratified by CNV size and type (deletion/duplication). (B) CNV burden of all rare CNVs, separated by clinical relevance (benign, uncertain, pathogenic) according to the American College of Medical Genetics guidelines (STAR Methods). Red boxes, odds ratios; Blue lines, 95% CIs. ORs > 1 represent an increase in risk for TS per CNV.

**Figure 4. Segmental and gene-based tests converge on two distinct loci significantly enriched in TS cases**
(A) Manhattan plot of segmental association test results representing genome-wide corrected p-values calculated at each CNV breakpoint. The two genome-wide significant association peaks correspond to deletions at *NRXN1* (P_locus=7.0×10⁻⁶, P_corr=1.0×10⁻³) and duplications at *CNTN6* (P_locus=5.4×10⁻⁵, P_corr =6.9×10⁻³). Red and blue levels correspond to a genome-wide corrected α of 0.05 and 0.01, respectively. (B) Heterozygous exonic deletions in *NRXN1* found in 12 cases (0.49%) and 1 control (0.03%), corresponding to an OR=20.2, 95% CI (2.6–155.2). Exon-affecting CNVs cluster at the 5′ end with deletions across exons 1–3 found in 10 cases and no controls. Red, deletions in TS cases; Dark Red, deletion in controls; Blue, case duplication. (C) Exon-spanning duplications over *CNTN6* found in 12 cases and 2 controls (OR=10.2, [2.0–17.8]) *CNTN6* duplications are considerably larger in cases compared to controls (640 vs. 143 kb, on average). Blue, case duplications; Dark blue, control duplications; Red, case deletion; Dark red, control duplication.

See this image and copyright information in PMC

Comment in

Complex genetics of Tourette's Syndrome: Piecing the puzzle.
Wagle Shukla A, Fox S. Wagle Shukla A, et al. Mov Disord. 2017 Dec;32(12):1685. doi: 10.1002/mds.27218. Epub 2017 Nov 13. Mov Disord. 2017. PMID: 29131391 No abstract available.

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Figures

Comment in

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Molecular Biology Databases

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