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Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette’s Syndrome and OCD
Dongmei Yu, M.S.; Carol A. Mathews, M.D.; Jeremiah M. Scharf, M.D., Ph.D.; Benjamin M. Neale, Ph.D.; Lea K. Davis, Ph.D.; Eric R. Gamazon, M.S.; Eske M. Derks, Ph.D.; Patrick Evans, Ph.D.; Christopher K. Edlund, M.S.; Jacquelyn Crane, M.D.; Jesen A. Fagerness, J.D.; Lisa Osiecki, B.A.; Patience Gallagher, B.S.; Gloria Gerber, B.A.; Stephen Haddad, M.S.; Cornelia Illmann, Ph.D.; Lauren M. McGrath, Ph.D.; Catherine Mayerfeld, B.A.; Sampath Arepalli, B.S.; Cristina Barlassina, B.B.Sc.; Cathy L. Barr, Ph.D.; Laura Bellodi, M.D.; Fortu Benarroch, M.D.; Gabriel Bedoya Berrió, M.Sc.; O. Joseph Bienvenu, M.D., Ph.D.; Donald W. Black, M.D.; Michael H. Bloch, M.D., M.S.; Helena Brentani, M.D., Ph.D.; Ruth D. Bruun, M.D.; Cathy L. Budman, M.D.; Beatriz Camarena, Ph.D.; Desmond D. Campbell, Ph.D.; Carolina Cappi, M.Sc.; Julio C. Cardona Silgado, M.Sc.; Maria C. Cavallini, M.D.; Denise A. Chavira, Ph.D.; Sylvain Chouinard, M.D.; Edwin H. Cook, M.D.; M.R. Cookson, Ph.D.; Vladimir Coric, M.D.; Bernadette Cullen, M.B., B.Ch.; Daniele Cusi, M.D.; Richard Delorme, M.D., Ph.D.; Damiaan Denys, M.D., Ph.D.; Yves Dion, M.D.; Valsama Eapen, F.R.A.N.Z.C.P., Ph.D.; Karin Egberts, M.D.; Peter Falkai, M.D.; Thomas Fernandez, M.D.; Eduardo Fournier, M.S.; Helena Garrido, M.A.; Daniel Geller, M.D.; Donald Gilbert, M.D.; Simon L. Girard, M.Sc.; Hans J. Grabe, M.D.; Marco A. Grados, M.D., M.P.H.; Benjamin D. Greenberg, M.D., Ph.D.; Varda Gross-Tsur, M.D.; Edna Grünblatt, Ph.D.; John Hardy, Ph.D.; Gary A. Heiman, Ph.D.; Sian M.J. Hemmings, Ph.D.; Luis D. Herrera, M.D., M.P.H.; Dianne M. Hezel; Pieter J. Hoekstra, M.D., Ph.D.; Joseph Jankovic, M.D.; James L. Kennedy, M.D.; Robert A. King, M.D.; Anuar I. Konkashbaev, M.S.; Barbara Kremeyer, Ph.D.; Roger Kurlan, M.D.; Nuria Lanzagorta, Psy.D.; Marion Leboyer, M.D., Ph.D.; James F. Leckman, M.D.; Leonhard Lennertz, M.Sc.; Chunyu Liu, Ph.D.; Christine Lochner, Ph.D.; Thomas L. Lowe, M.D.; Sara Lupoli, Ph.D.; Fabio Macciardi, M.D., Ph.D.; Wolfgang Maier, M.D.; Paolo Manunta, M.D.; Maurizio Marconi, M.D.; James T. McCracken, M.D.; Sandra C. Mesa Restrepo, M.D.; Rainald Moessner, M.D.; Priya Moorjani, Ph.D.; Jubel Morgan, R.N.; Heike Muller, M.Sc.; Dennis L. Murphy, M.D.; Allan L. Naarden, M.D.; Erika Nurmi, M.D., Ph.D.; William Cornejo Ochoa, M.D.; Roel A. Ophoff, Ph.D.; Andrew J. Pakstis, Ph.D.; Michele T. Pato, M.D.; Carlos N. Pato, M.D., Ph.D.; John Piacentini, Ph.D., A.B.P.P.; Christopher Pittenger, M.D., Ph.D.; Yehuda Pollak, Ph.D.; Scott L. Rauch, M.D.; Tobias Renner, M.D.; Victor I. Reus, M.D.; Margaret A. Richter, M.D.; Mark A. Riddle, M.D.; Mary M. Robertson, M.D., D.Sc.(Med); Roxana Romero, M.A.; Maria C. Rosário, M.D., Ph.D.; David Rosenberg, M.D.; Stephan Ruhrmann, M.D.; Chiara Sabatti, Ph.D.; Erika Salvi, Ph.D.; Aline S. Sampaio, M.D., Ph.D.; Jack Samuels, Ph.D.; Paul Sandor, M.D.; Susan K. Service, M.S.; Brooke Sheppard, Sc.M.; Harvey S. Singer, M.D.; Jan H. Smit, Ph.D.; Dan J. Stein, M.D., Ph.D.; Eric Strengman, M.Sc.; Jay A. Tischfield, Ph.D.; Maurizio Turiel, M.D.; Ana V. Valencia Duarte, Ph.D.; Homero Vallada, M.D., Ph.D.; Jeremy Veenstra-VanderWeele, M.D.; Susanne Walitza, M.D.; Ying Wang, M.Sc.; Mike Weale, Ph.D.; Robert Weiss, Ph.D.; Jens R. Wendland, M.D.; Herman G.M. Westenberg, Ph.D.; Yin Yao Shugart, Ph.D.; Ana G. Hounie, M.D., Ph.D.; Euripedes C. Miguel, M.D., Ph.D.; Humberto Nicolini, M.D., Ph.D.; Michael Wagner, Ph.D.; Andres Ruiz-Linares, M.D., Ph.D.; Danielle C. Cath, M.D.; William McMahon, M.D.; Danielle Posthuma, Ph.D.; Ben A. Oostra, Ph.D.; Gerald Nestadt, M.D.; Guy A. Rouleau, M.D.; Shaun Purcell, Ph.D.; Michael A. Jenike, M.D.; Peter Heutink, Ph.D.; Gregory L. Hanna, M.D.; David V. Conti, Ph.D.; Paul D. Arnold, M.D., Ph.D.; Nelson B. Freimer, M.D.; S. Evelyn Stewart, M.D.; James A. Knowles, M.D., Ph.D.; Nancy J. Cox, Ph.D.; David L. Pauls, Ph.D.
Am J Psychiatry 2014;:. doi:10.1176/appi.ajp.2014.13101306
View Author and Article Information

The first three authors and the last four authors contributed equally to this work.

Dr. Westenberg is deceased.

Dr. Scharf has received research support and travel support from the Tourette Syndrome Association (TSA); he also serves on the TSA Scientific Advisory Board. Dr. Black receives research support from AstraZeneca and royalties from American Psychiatric Publishing, Oxford University Press, and UpToDate. Dr. Budman has received research grant support from Psyadon, AstraZeneca, and Otsuka, and has served as a speaker for the National Tourette Syndrome Association-CDC Partnership. Dr. Cook served as a consultant and was a site principal investigator for a Seaside Therapeutics clinical trial in autism spectrum disorder. Dr. Coric is an employee of Bristol-Myers Squibb and owns stock in the company; his regarding this study stems from his work at Yale University, and no financial or other support for this study was obtained from Bristol-Myers Squibb. Dr. Denys received a grant from the U.S. national Tourette Syndrome Association; he is a member of the advisory board of Lundbeck and he receives consultant fees from Medtronic for educational purposes. Dr. Fernandez has received research funding from NIMH, the Simons Foundation, the Allison Foundation, and Shire. Dr. Gilbert has served as a site investigator for clinical trials in Tourette’s syndrome for Otsuka, Psyadon, and AstraZeneca. Dr. Grabe has received research support from the German Research Foundation, the Federal Ministry of Education, and Research Germany and has received speaking honoraria from Servier and Eli Lilly. Dr. Hardy has served as a consultant for Eisai and has been on speakers bureaus for Takeda, Eli Lilly, and Roche. Dr. Kennedy has received honoraria from Roche, Novartis, and Eli Lilly; he serves as an non-paid member of AssureRx Health Scientific Advisory Board. Dr. Leckman has received research support from NIH, the Tourette Syndrome Association, Grifols, and Klingenstein Third Generation Foundation, and royalties from John Wiley & Sons, McGraw-Hill, Oxford University Press. Dr. Piacentini has received research support from Pfizer Pharmaceuticals via the Duke University Clinical Research Institute and from the Tourette Syndrome Association; speaking/travel support from the Tourette Syndrome Association and the International OCD Foundation; financial support from the Pettit Family Foundation; and royalties from Oxford University Press and Guilford Press. Dr. Pittenger has served as a consultant for Roche. Dr. Rauch has participated in research funded by Medtronic and Cyberonics. Dr. Richter has received speaking honoraria from Lundbeck. Dr. Robertson has received support from the U.K. Tourette Syndrome Association, the U.S. Tourette Syndrome Association, and COST/ESSTS (the European Society for the Study of Tourette Syndrome); speaking honoraria from Janssen-Cilag and Flynn Pharma; and royalties from Wiley-Blackwell, Oxford University Press, David Fulton/Granada/Taylor Francis, and Jessica Kingsley Publishers. Dr. Rosário has served on speakers bureaus for Novartis and Shire. Dr. Rosenberg has served as a consultant for Shire. Dr. Ruhrmann has received speaking honoraria from Roche, Otsuka, Lundbeck, and Johnson & Johnson and travel funds from Roche and Servier. Dr. Sandor has received research support from Otsuka and speaking honoraria from Purdue Pharma. Dr. Stein has received research grants from and/or served as a consultant to AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun. Dr. Veenstra-VanderWeele has served as a consultant for Novartis, Roche, and SynapDx and received research funding from Novartis, Roche, SynapDx, Seaside Therapeutics, Forest, and Sunovion. Dr. Walitza has received speaking honoraria from Janssen Cilag, AstraZeneca, and Eli Lilly. Dr. Wendland is a former employee of Hoffmann-La Roche (2010–2012) and is now an employee of Pfizer (2012–present). Dr. Nicolini has received research funds from Pherin Pharmaceuticals, Transcept Pharmaceuticals, and EnVivo and speaking honoraria from MSD and Landsteiner Mexico. Dr. Arnold has received an unrestricted research grant from DNA Genotek. Dr. Knowles received a speaking honorarium from Illumina, Inc. Dr. McCracken has received research support from and/or served as a consultant to Roche, Seaside Therapeutics, and BioMarin. The other authors report no financial relationships with commercial interests.

Supported by a grant from the David Judah Fund; NIH grant NS40024 to Drs. Pauls and Scharf; the Tourette Syndrome Association International Consortium for Genetics; NIH grants NS16648, MH079489, and MH073250 to Dr. Pauls; NIH grant NS037484 to Dr. Freimer; a grant from the Tourette Syndrome Association and NIH grant MH085057 to Dr. Scharf, grant MH079494 to Dr. Knowles, MH71507 to Dr. McCracken; the OCD Collaborative Genetics Association Study, which supported the imputation; an American Academy of Child and Adolescent Psychiatry Early Investigator Research Grant, an Anxiety Disorders Association of America Junior Investigator Research Grant, the University of British Columbia, and a Michael Smith Foundation Clinical Research Scholar Award to Dr. Stewart; American Recovery and Reinvestment Act awards NS40024-07S1 to Drs. Pauls and Scharf and NS16648-29S1 to Dr. Pauls. Additional support for analysis was provided by grants R01 MH090937 and P50MH094267 to Dr. Cox and by grant P30NS062691 from the UCLA Informatics Center for Neurogenetics and Neurogenomics to Dr. Freimer. Dr. Heiman and Dr. Tischfield received support from the New Jersey Center for Tourette Syndrome and Associated Disorders and NIMH grant R01MH092293. Dr. Stein and Dr. Lochner are supported by the Medical Research Council of South Africa. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment, and Health Initiative [GEI] (grant U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (grant U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (grant U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (grant P01 CA089392), and the Family Study of Cocaine Dependence (grant R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (grant U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High Throughput Genotyping for Studying the Genetic Contributions to Human Disease” (grant HHSN268200782096C). The data sets used for the analyses in this study were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. The European Union (grant FP7-HEALTH-2007-A-201550), HYPERGENES, and InterOmics (PB05 MIUR-CNR Italian Flagship Project) provided financial support for the genotyping of Italian controls.

From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; the Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; the Department of Psychiatry, University of California, San Francisco; the Department of Neurology, Massachusetts General Hospital, Boston; the Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, Boston; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles; the Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Md.; the Genomic and Bioinformatic Unit, Filarete Foundation, Milan, Italy; the Department of Health Sciences, Graduate School of Nephrology, University of Milan, Milan; the Toronto Western Research Institute, University Health Network, Toronto; Hospital for Sick Children, Toronto; Università Vita-Salute San Raffaele, Milan; the Herman Dana Division of Child and Adolescent Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem; Universidad de Antioquia, Universidad Pontificia Bolivariana, Medellín, Colombia; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; the Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; North Shore-Long Island Jewish Medical Center and North Shore-Long Island Jewish Health System, Manhasset, N.Y.; New York University Medical Center, New York; Hofstra University School of Medicine, Hempstead, N.Y.; Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz, Mexico City; University College London, London; the Department of Psychiatry, University of Hong Kong, Hong Kong; Ospedale San Raffaele, Milan; the Department of Psychiatry, University of California San Diego, La Jolla; the Department of Psychology, University of California Los Angeles; Montreal Neurological Institute, McGill University, Montreal; the Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago; Human Genetics and Cognitive Functions, Institut Pasteur, Paris; Fondation FondaMental, French National Science Foundation, Créteil, France; AP-HP, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris; Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam; the Department of Psychiatry, University of Montreal, Montreal; Infant Child and Adolescent Psychiatry, University of New South Wales, Australia; Academic Unit of Child Psychiatry, South West Sydney Local Health District (AUCS), Australia; Department of Child and Adolescent Psychiatry and Psychotherapy, University of Tübingen, Germany; the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany; the Department of Psychiatry and Psychotherapy, University of Munich, Munich; Hospital Nacional de Niños, San Jose, Costa Rica; Clinica Herrera Amighetti, Avenida Escazú, San Jose, Costa Rica; OCD Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati; the Department of Psychiatry and Psychotherapy, Helios-Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany; the Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Providence, R.I.; Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem; the University Clinics of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland; the Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway; the Department of Psychiatry, University of Stellenbosch, Stellenbosch, South Africa; the Department of Psychiatry, University Medical Center, University of Groningen, Groningen, the Netherlands; Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston; the Neurogenetics Section, Centre for Addiction and Mental Health, Toronto; the Department of Psychiatry, University of Toronto, Toronto; Atlantic Neuroscience Institute, Overlook Hospital, Summit, N.J.; Carracci Medical Group, Mexico City; Institut Mondor de Recherche Biomédicale, Psychiatric Genetics, Créteil, France; the Department of Psychiatry and Psychotherapy, University of Bonn, Bonn; the Department of Psychiatry, Institute of Human Genetics, University of Illinois at Chicago; MRC Unit on Anxiety and Stress Disorders, Departments of Psychiatry, University of Stellenbosch and University of Cape Town, South Africa; the Department of Psychiatry and Human Behavior, School of Medicine, University of California Irvine; Università Vita Salute San Raffaele and IRCCS San Raffaele Scientific Institute, Milan; the Center of Transfusion Medicine and Immunohematology, Foundation IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan; the Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles; David Geffen School of Medicine, Los Angeles; Department of Biological Sciences, Columbia University, New York; University of Utah, Salt Lake City; Laboratory of Clinical Science, NIMH Intramural Research Program, Bethesda, Md.; the Department of Clinical Research, Medical City Dallas Hospital, Dallas; the Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands; the Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles; the Department of Genetics, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry and Behavioral Sciences, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles; Partners Psychiatry and McLean Hospital, Boston; the Frederick W. Thompson Anxiety Disorders Centre, Sunnybrook Health Sciences Centre, Toronto; St. George’s Hospital and Medical School, London; the Child and Adolescent Psychiatry Unit, Department of Psychiatry, Federal University of São Paulo, Brazil; the Department of Psychiatry and Behavioral Neurosciences, Wayne State University and the Detroit Medical Center, Detroit; the Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany; the Department of Health Research and Policy, Stanford University, Stanford; University Health Care Services-SMURB, Universidade Federal da Bahia, Salvador, Bahia, Brazil; the Department of Psychiatry, University of Toronto and University Health Network, Toronto Western Research Institute and Youthdale Treatment Centers, Toronto; Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, VU University Medical Center, Amsterdam; University of Cape Town, Cape Town, South Africa; the Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; the Department of Health Technologies, University of Milan, Milan; the Departments of Psychiatry, Pediatrics, and Pharmacology, Kennedy Center for Research on Human Development, and Brain Institute, Vanderbilt University, Nashville, Tenn.; the Department of Child and Adolescent Psychiatry, University of Würzburg, Würzburg, Germany; the Division of Child and Adolescent Psychiatry, Department of Psychiatry, Weill Cornell Medical Center, New York; the Department of Medical and Molecular Genetics, King’s College London, London; the Department of Psychiatry, Academic Medical Center and Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam; Unit on Statistical Genomics, NIMH Intramural Research Program, Bethesda, Md.; National Institute of Genomic Medicine-SAP, Carracci Medical Group, Mexico City; the Department of Clinical and Health Psychology, Utrecht University, Utrecht, the Netherlands; the Department of Psychiatry, University of Utah, Salt Lake City; Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Center, Amsterdam; the Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam; the Department of Child and Adolescent Psychiatry and the Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Mt. Sinai Medical Center, New York; the German Center for Neurodegenerative Diseases, Tübingen; the Department of Psychiatry, University of Michigan, Ann Arbor; Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto; British Columbia Mental Health and Addictions Research Institute, University of British Columbia, Vancouver.

Address correspondence to Ms. Yu (dyu@pngu.mgh.harvard.edu) and Dr. Pauls (dpauls@pngu.mgh.harvard.edu).

Copyright © 2014 by the American Psychiatric Association

Received October 02, 2013; Revised April 04, 2014; Accepted May 23, 2014.

Abstract

Objective  Obsessive-compulsive disorder (OCD) and Tourette’s syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette’s syndrome and OCD.

Method  The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette’s syndrome, 579 with OCD plus Tourette’s syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.

Results  Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10−4), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette’s syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette’s syndrome/chronic tics were included in the analysis (p=0.01).

Conclusions  Previous work has shown that Tourette’s syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette’s syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Abstract Teaser
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FIGURE 1. Manhattan Plot of All Genotyped and Imputed Single-Nucleotide Polymorphisms for 3,013 Tourette’s Syndrome-Obsessive-Compulsive Disorder European Ancestry Cases and 5,957 Controlsa

a Red and blue lines indicate significance thresholds of 5×10−8 and 1×10−5, respectively.

FIGURE 2. Q-Q Plot of Nominal Disease Association p Values Versus Expected p Values Among the Cis eQTLs and mQTLs in Different Brain Tissues in the Tourette’s Syndrome, Obsessive-Compulsive Disorder (OCD), and Combined Genome-Wide Association Study (GWAS)a

a eQTL=expression quantitative trait locus; mQTL=methylation quantitative trait locus. A horizontal shift to the left from the diagonal line (of complete concordance between the observed p values and expected p values under the null hypothesis of no enrichment) in the Q-Q plot indicates enrichment. Red dots represent cerebellum mQTLs, green dots represent cerebellum eQTLs, black dots represent frontal cortex eQTLs, and blue dots represent parietal cortex eQTLs.

FIGURE 3. Individual Disorder and Cross-Disorder Polygenic Score Analysis in Tourette’s Syndrome and Obsessive-Compulsive Disorder (OCD)a

a The variance explained in two target samples (OCD European ancestry [EU] parent-child trios and Tourette’s French Canadian [FC] cases and matching controls) is based on risk scores derived from an aggregated sum of weighted single-nucleotide polymorphism risk allele effect sizes estimated from discovery samples at six significance thresholds. The y axis indicates Nagelkerke’s pseudo R2. The p value under each discovery sample indicates how well the risk scores derived from the discovery sample can predict the illness phenotype in the target sample. N is the number of cases in each discovery sample. Negative R2 values indicate a negative correlation between risk scores and illness status in the target sample. OCD EU without known Tourette’s/chronic tics=European-ancestry OCD genome-wide association study (GWAS) samples after removing samples with known co-occurring Tourette’s/chronic tics; all OCD EU=European-ancestry OCD GWAS samples plus additional EU GWAS samples with co-occurring OCD and Tourette’s/chronic tics; combined Tourette’s/OCD EU=all European-ancestry Tourette’s GWAS samples and OCD GWAS samples; downsized OCD EU=randomly selected subset of OCD EU samples to match the number of cases in the Tourette’s EU discovery sample; Tourette’s EU=European-ancestry Tourette’s GWAS samples; OCD EU trios=the OCD EU parent-child trio probands and matched pseudo-control data derived from nontransmitted alleles; Tourette’s FC=Tourette’s French Canadian cases and matching controls. A permutation test was carried out to determine the significance of the difference in R2 between risk scores derived from OCD EU without known Tourette’s/chronic tics and all OCD EU, resulting in a two-sided empirical p value of 0.01. The inset box at upper right demonstrates the risk score elevations (difference in risk scores of transmitted alleles and untransmitted alleles in the OCD EU trios, standardized by the risk score of the untransmitted alleles) derived from three discovery samples: OCD EU without known Tourette’s/chronic tics, all OCD EU, and combined Tourette’s/OCD EU. Two-sided paired t tests were conducted for the pairwise comparisons of risk score elevations derived from three discovery samples.

Anchor for Jump
TABLE 1.Genomic Regions With p<1×10–5 in the Combined Tourette’s Syndrome-Obsessive-Compulsive Disorder (OCD) Genome-Wide Association Study (GWAS)a
Table Footer Note

a Chr=chromosome; SNP=single-nucleotide polymorphism; A1=reference allele; A2=alternative allele; A1 FRQ=frequency of A1 allele in the European-ancestry control samples; number of SNPs in LD=number of additional SNPs in linkage disequilibrium with association p values <1×10–3 (LD defined as r2>0.5). Complete annotation of these SNPs as well as all SNPs with association p values <1×10–3 is provided in Tables S1 and S2 in the online data supplement.

Anchor for Jump
TABLE 2.Number of Associated eQTLs/mQTLs With False Discovery Rate <0.25 in the Tourette’s Syndrome, Obsessive-Compulsive Disorder (OCD), and Combined Genome-Wide Association Study (GWAS)a
Table Footer Note

a eQTL=expression quantitative trait locus; mQTL=methylation quantitative trait locus. Number of loci indicates the number of LD-independent loci among the identified eQTLs.

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