Meta-Analysis

. 2019 Mar 1;176(3):217-227.

doi: 10.1176/appi.ajp.2018.18070857.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Dongmei Yu¹, Jae Hoon Sul¹, Fotis Tsetsos¹, Muhammad S Nawaz¹, Alden Y Huang¹, Ivette Zelaya¹, Cornelia Illmann¹, Lisa Osiecki¹, Sabrina M Darrow¹, Matthew E Hirschtritt¹, Erica Greenberg¹, Kirsten R Muller-Vahl¹, Manfred Stuhrmann¹, Yves Dion¹, Guy Rouleau¹, Harald Aschauer¹, Mara Stamenkovic¹, Monika Schlögelhofer¹, Paul Sandor¹, Cathy L Barr¹, Marco Grados¹, Harvey S Singer¹, Markus M Nöthen¹, Johannes Hebebrand¹, Anke Hinney¹, Robert A King¹, Thomas V Fernandez¹, Csaba Barta¹, Zsanett Tarnok¹, Peter Nagy¹, Christel Depienne¹, Yulia Worbe¹, Andreas Hartmann¹, Cathy L Budman¹, Renata Rizzo¹, Gholson J Lyon¹, William M McMahon¹, James R Batterson¹, Danielle C Cath¹, Irene A Malaty¹, Michael S Okun¹, Cheston Berlin¹, Douglas W Woods¹, Paul C Lee¹, Joseph Jankovic¹, Mary M Robertson¹, Donald L Gilbert¹, Lawrence W Brown¹, Barbara J Coffey¹, Andrea Dietrich¹, Pieter J Hoekstra¹, Samuel Kuperman¹, Samuel H Zinner¹, Pétur Luðvigsson¹, Evald Sæmundsen¹, Ólafur Thorarensen¹, Gil Atzmon¹, Nir Barzilai¹, Michael Wagner¹, Rainald Moessner¹, Roel Ophoff¹, Carlos N Pato¹, Michele T Pato¹, James A Knowles¹, Joshua L Roffman¹, Jordan W Smoller¹, Randy L Buckner¹, A Jeremy Willsey¹, Jay A Tischfield¹, Gary A Heiman¹, Hreinn Stefansson¹, Kári Stefansson¹, Danielle Posthuma¹, Nancy J Cox¹, David L Pauls¹, Nelson B Freimer¹, Benjamin M Neale¹, Lea K Davis¹, Peristera Paschou¹, Giovanni Coppola¹, Carol A Mathews¹, Jeremiah M Scharf¹; Tourette Association of America International Consortium for Genetics, the Gilles de la Tourette GWAS Replication Initiative, the Tourette International Collaborative Genetics Study, and the Psychiatric Genomics Consortium Tourette Syndrome Working Group¹

Affiliations

Affiliation

¹ The Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston (Yu, Illmann, Osiecki, Smoller, Pauls, Neale, Scharf); the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass. (Yu, Neale, Scharf); the Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles (Sul, Huang, Zelaya, Ophoff, Freimer, Coppola); the Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles (Sul, Huang, Zelaya, Freimer, Coppola); the Department of Molecular Biology and Genetics, Democritus University of Thrace, Xanthi, Greece (Tsetsos); the Department of Biological Sciences, Purdue University, West Lafayette, Ind. (Tsetsos, Paschou); deCODE Genetics/Amgen, Reykjavik, Iceland (Nawaz, H. Stefansson, K. Stefansson); the Bioinformatics Interdepartmental Program, University of California, Los Angeles (Huang, Zelaya); the Department of Psychiatry, University of California, San Francisco (Darrow); the Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco (Hirschtritt, Willsey); the Department of Psychiatry, Massachusetts General Hospital, Boston (Greenberg, Roffman, Buckner); the Clinic of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany (Muller-Vahl); the Institute of Human Genetics, Hannover Medical School, Hannover, Germany (Stuhrmann); McGill University Health Center, University of Montreal, McGill University Health Centre, Montreal (Dion); the Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal (Rouleau); the Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna (Aschauer, Stamenkovic); Biopsychosocial Corporation, Vienna (Aschauer, Schlögelhofer); University Health Network, Youthdale Treatment Centres, and University of Toronto, Toronto (Sandor); the Krembil Research Institute, University Health Network, Hospital for Sick Children, and University of Toronto, Toronto (Barr); Johns Hopkins University School of Medicine, Baltimore (Grados, Singer); the Institute of Human Genetics, University Hospital Bonn, University of Bonn Medical School, Bonn, Germany (Nöthen); the Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany (Hebebrand, Hinney); the Yale Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (King, Fernandez); the Institute of Medical Chemistry, Molecular Biology, and Pathobiochemistry, Semmelweis University, Budapest, Hungary (Barta); Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary (Tarnok, Nagy); the Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany (Depienne); Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris (Depienne, Worbe, Hartmann); French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris (Worbe, Hartmann); Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris (Worbe, Hartmann); Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York (Budman); Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy (Rizzo); the Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (Lyon); the Department of Psychiatry, University of Utah, Salt Lake City (McMahon); Children's Mercy Hospital, Kansas City, Mo. (Batterson); the Department of Psychiatry, University Medical Center Groningen and Rijksuniversity Groningen, and Drenthe Mental Health Center, Groningen, the Netherlands (Cath); the Department of Neurology, Fixel Center for Neurological Diseases, McKnight Brain Institute, University of Florida, Gainesville (Malaty, Okun); Pennsylvania State University College of Medicine, Hershey (Berlin); Marquette University and University of Wisconsin-Milwaukee, Milwaukee (Woods); Tripler Army Medical Center and University of Hawaii John A. Burns School of Medicine, Honolulu (Lee); Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston (Jankovic); the Division of Psychiatry, Department of Neuropsychiatry, University College London (Robertson); the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati (Gilbert); Children's Hospital of Philadelphia, Philadelphia (Brown); the Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami (Coffey); the Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Dietrich, Hoekstra); University of Iowa Carver College of Medicine, Iowa City (Kuperman); the Department of Pediatrics, University of Washington, Seattle (Zinner); the Department of Pediatrics, Landspitalinn University Hospital, Reykjavik, Iceland (Luðvigsson, Thorarensen); the Faculty of Medicine, University of Iceland, Reykjavík, Iceland (Sæmundsen, Stefansson); the State Diagnostic and Counselling Centre, Kópavogur, Iceland (Sæmundsen); the Department of Genetics and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (Atzmon, Barzilai); the Department of Human Biology, Haifa University, Haifa, Israel (Atzmon); the Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany (Wagner); the Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany (Moessner); SUNY Downstate Medical Center Brooklyn, New York (C.M. Pato, M.T. Pato, Knowles); the Athinoula A. Martinos Center for Biomedical Research, Department of Radiology, Massachusetts General Hospital, Charlestown (Roffman, Buckner); the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Smoller); the Center for Brain Science and Department of Psychology, Harvard University, Cambridge, Mass. (Buckner); the Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco (Willsey); the Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway (Tischfield, Heiman); the Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam (Posthuma); the Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tenn. (Cox, Davis); the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston (Neale); the Department of Psychiatry, Genetics Institute, University of Florida, Gainesville (Mathews); and the Department of Neurology, Brigham and Women's Hospital, and the Department of Neurology, Massachusetts General Hospital, Boston (Scharf).

PMID: 30818990
PMCID: PMC6677250
DOI: 10.1176/appi.ajp.2018.18070857

Meta-Analysis

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Dongmei Yu et al. Am J Psychiatry. 2019.

. 2019 Mar 1;176(3):217-227.

doi: 10.1176/appi.ajp.2018.18070857.

Authors

Affiliation

¹ The Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston (Yu, Illmann, Osiecki, Smoller, Pauls, Neale, Scharf); the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass. (Yu, Neale, Scharf); the Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles (Sul, Huang, Zelaya, Ophoff, Freimer, Coppola); the Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles (Sul, Huang, Zelaya, Freimer, Coppola); the Department of Molecular Biology and Genetics, Democritus University of Thrace, Xanthi, Greece (Tsetsos); the Department of Biological Sciences, Purdue University, West Lafayette, Ind. (Tsetsos, Paschou); deCODE Genetics/Amgen, Reykjavik, Iceland (Nawaz, H. Stefansson, K. Stefansson); the Bioinformatics Interdepartmental Program, University of California, Los Angeles (Huang, Zelaya); the Department of Psychiatry, University of California, San Francisco (Darrow); the Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco (Hirschtritt, Willsey); the Department of Psychiatry, Massachusetts General Hospital, Boston (Greenberg, Roffman, Buckner); the Clinic of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany (Muller-Vahl); the Institute of Human Genetics, Hannover Medical School, Hannover, Germany (Stuhrmann); McGill University Health Center, University of Montreal, McGill University Health Centre, Montreal (Dion); the Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal (Rouleau); the Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna (Aschauer, Stamenkovic); Biopsychosocial Corporation, Vienna (Aschauer, Schlögelhofer); University Health Network, Youthdale Treatment Centres, and University of Toronto, Toronto (Sandor); the Krembil Research Institute, University Health Network, Hospital for Sick Children, and University of Toronto, Toronto (Barr); Johns Hopkins University School of Medicine, Baltimore (Grados, Singer); the Institute of Human Genetics, University Hospital Bonn, University of Bonn Medical School, Bonn, Germany (Nöthen); the Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany (Hebebrand, Hinney); the Yale Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (King, Fernandez); the Institute of Medical Chemistry, Molecular Biology, and Pathobiochemistry, Semmelweis University, Budapest, Hungary (Barta); Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary (Tarnok, Nagy); the Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany (Depienne); Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris (Depienne, Worbe, Hartmann); French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris (Worbe, Hartmann); Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris (Worbe, Hartmann); Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York (Budman); Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy (Rizzo); the Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (Lyon); the Department of Psychiatry, University of Utah, Salt Lake City (McMahon); Children's Mercy Hospital, Kansas City, Mo. (Batterson); the Department of Psychiatry, University Medical Center Groningen and Rijksuniversity Groningen, and Drenthe Mental Health Center, Groningen, the Netherlands (Cath); the Department of Neurology, Fixel Center for Neurological Diseases, McKnight Brain Institute, University of Florida, Gainesville (Malaty, Okun); Pennsylvania State University College of Medicine, Hershey (Berlin); Marquette University and University of Wisconsin-Milwaukee, Milwaukee (Woods); Tripler Army Medical Center and University of Hawaii John A. Burns School of Medicine, Honolulu (Lee); Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston (Jankovic); the Division of Psychiatry, Department of Neuropsychiatry, University College London (Robertson); the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati (Gilbert); Children's Hospital of Philadelphia, Philadelphia (Brown); the Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami (Coffey); the Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Dietrich, Hoekstra); University of Iowa Carver College of Medicine, Iowa City (Kuperman); the Department of Pediatrics, University of Washington, Seattle (Zinner); the Department of Pediatrics, Landspitalinn University Hospital, Reykjavik, Iceland (Luðvigsson, Thorarensen); the Faculty of Medicine, University of Iceland, Reykjavík, Iceland (Sæmundsen, Stefansson); the State Diagnostic and Counselling Centre, Kópavogur, Iceland (Sæmundsen); the Department of Genetics and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (Atzmon, Barzilai); the Department of Human Biology, Haifa University, Haifa, Israel (Atzmon); the Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany (Wagner); the Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany (Moessner); SUNY Downstate Medical Center Brooklyn, New York (C.M. Pato, M.T. Pato, Knowles); the Athinoula A. Martinos Center for Biomedical Research, Department of Radiology, Massachusetts General Hospital, Charlestown (Roffman, Buckner); the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Smoller); the Center for Brain Science and Department of Psychology, Harvard University, Cambridge, Mass. (Buckner); the Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco (Willsey); the Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway (Tischfield, Heiman); the Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam (Posthuma); the Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tenn. (Cox, Davis); the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston (Neale); the Department of Psychiatry, Genetics Institute, University of Florida, Gainesville (Mathews); and the Department of Neurology, Brigham and Women's Hospital, and the Department of Neurology, Massachusetts General Hospital, Boston (Scharf).

PMID: 30818990
PMCID: PMC6677250
DOI: 10.1176/appi.ajp.2018.18070857

Abstract

Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity.

Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined.

Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects.

Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Keywords: Child Psychiatry; Genetics; Genome-Wide Association Study; Tic Disorders; Tourette Syndrome.

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Figures

**Figure 1.**
Results of the primary Tourette Syndrome GWAS meta-analysis of 4,819 cases and 9,488 controls.

**Figure 2.**
Density plot demonstrating the distribution of Tourette syndrome polygenic risk scores (PRS) in population-based Icelandic Tourette cases (purple), tic disorder cases (blue), unscreened population controls (green), and tic negative population controls (orange).

**Figure 3.**
Gene expression enrichment analysis of genome-wide Tourette syndrome polygenic risk in 53 adult human tissues.

See this image and copyright information in PMC

References

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Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Affiliation

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Authors

Affiliation

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous