Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome.

GWAS Meta-analysis NR2F1 Tourette syndrome

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
02 Feb 2023
Historique:
received: 11 05 2022
revised: 23 11 2022
accepted: 24 01 2023
pubmed: 5 2 2023
medline: 5 2 2023
entrez: 4 2 2023
Statut: aheadofprint

Résumé

Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Sections du résumé

BACKGROUND BACKGROUND
Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year.
METHODS METHODS
We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants.
RESULTS RESULTS
We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume.
CONCLUSIONS CONCLUSIONS
Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Identifiants

DOI: 10.1016/j.biopsych.2023.01.023 PMID: 36738982
pubmed: 36738982
pii: S0006-3223(23)00051-3
doi: 10.1016/j.biopsych.2023.01.023
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NIMH NIH HHS
ID : R01 MH115958
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105746
Pays : United States

Investigateurs

Cathy L Barr (CL)
James R Batterson (JR)
Cheston Berlin (C)
Cathy L Budman (CL)
Giovanni Coppola (G)
Nancy J Cox (NJ)
Sabrina Darrow (S)
Yves Dion (Y)
Nelson B Freimer (NB)
Marco A Grados (MA)
Erica Greenberg (E)
Matthew E Hirschtritt (ME)
Alden Y Huang (AY)
Cornelia Illmann (C)
Robert A King (RA)
Roger Kurlan (R)
James F Leckman (JF)
Gholson J Lyon (GJ)
Irene A Malaty (IA)
William M McMahon (WM)
Benjamin M Neale (BM)
Michael S Okun (MS)
Lisa Osiecki (L)
Mary M Robertson (MM)
Guy A Rouleau (GA)
Paul Sandor (P)
Harvey S Singer (HS)
Jan H Smit (JH)
Jae Hoon Sul (JH)
Christos Androutsos (C)
Entela Basha (E)
Luca Farkas (L)
Jakub Fichna (J)
Piotr Janik (P)
Mira Kapisyzi (M)
Iordanis Karagiannidis (I)
Anastasia Koumoula (A)
Peter Nagy (P)
Joanna Puchala (J)
Natalia Szejko (N)
Urszula Szymanska (U)
Vaia Tsironi (V)
Alan Apter (A)
Juliane Ball (J)
Benjamin Bodmer (B)
Emese Bognar (E)
Judith Buse (J)
Marta Correa Vela (MC)
Carolin Fremer (C)
Blanca Garcia-Delgar (B)
Mariangela Gulisano (M)
Annelieke Hagen (A)
Julie Hagstrøm (J)
Marcos Madruga-Garrido (M)
Peter Nagy (P)
Alessandra Pellico (A)
Daphna Ruhrman (D)
Jaana Schnell (J)
Paola Rosaria Silvestri (PR)
Liselotte Skov (L)
Tamar Steinberg (T)
Friederike Tagwerker Gloor (FT)
Victoria L Turner (VL)
Elif Weidinger (E)
John Alexander (J)
Tamas Aranyi (T)
Wim R Buisman (WR)
Jan K Buitelaar (JK)
Nicole Driessen (N)
Petros Drineas (P)
Siyan Fan (S)
Natalie J Forde (NJ)
Sarah Gerasch (S)
Odile A van den Heuvel (OA)
Cathrine Jespersgaard (C)
Ahmad S Kanaan (AS)
Harald E Möller (HE)
Muhammad S Nawaz (MS)
Ester Nespoli (E)
Luca Pagliaroli (L)
Geert Poelmans (G)
Petra J W Pouwels (PJW)
Francesca Rizzo (F)
Dick J Veltman (DJ)
Ysbrand D van der Werf (YD)
Joanna Widomska (J)
Nuno R Zilhäo (NR)
Lawrence W Brown (LW)
Keun-Ah Cheon (KA)
Barbara J Coffey (BJ)
Thomas V Fernandez (TV)
Blanca Garcia-Delgar (B)
Donald L Gilbert (DL)
Julie Hagstrøm (J)
Hyun Ju Hong (HJ)
Laura Ibanez-Gomez (L)
Eun-Joo Kim (EJ)
Young Key Kim (YK)
Young-Shin Kim (YS)
Robert A King (RA)
Yun-Joo Koh (YJ)
Sodahm Kook (S)
Samuel Kuperman (S)
Bennett L Leventhal (BL)
Marcos Madruga-Garrido (M)
Athanasios Maras (A)
Tara L Murphy (TL)
Eun-Young Shin (EY)
Dong-Ho Song (DH)
Jungeun Song (J)
Matthew W State (MW)
Frank Visscher (F)
Sheng Wang (S)
Samuel H Zinner (SH)

Informations de copyright

Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Auteurs

Fotis Tsetsos (F)

Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.

Apostolia Topaloudi (A)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana.

Pritesh Jain (P)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana.

Zhiyu Yang (Z)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana.

Dongmei Yu (D)

Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Petros Kolovos (P)

Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.

Zeynep Tumer (Z)

Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Renata Rizzo (R)

Child and Adolescent Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Andreas Hartmann (A)

Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France.

Christel Depienne (C)

Institute for Human Genetics, University Hospital Essen, Essen, Germany.

Yulia Worbe (Y)

Assistance Publique Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France; French Reference Centre for Gilles de la Tourette Syndrome, Sorbonne University, Faculty of Medicine, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Kirsten R Müller-Vahl (KR)

Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.

Danielle C Cath (DC)

Department of Clinical and Health Psychology, Utrecht University, Utrecht, Netherlands.

Dorret I Boomsma (DI)

Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany; EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, the Netherlands.

Tomasz Wolanczyk (T)

Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.

Cezary Zekanowski (C)

Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.

Csaba Barta (C)

Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis Egyetem, Budapest, Hungary.

Zsofia Nemoda (Z)

Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis Egyetem, Budapest, Hungary.

Zsanett Tarnok (Z)

Vadaskert Clinic for Child and Adolescent Psychiatry, Budapest, Hungary.

Shanmukha S Padmanabhuni (SS)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana.

Joseph D Buxbaum (JD)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Dorothy Grice (D)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Tics, OCD, and Related Disorders, Icahn School of Medicine at Mount Sinai, New York, New York.

Jeffrey Glennon (J)

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.

Hreinn Stefansson (H)

deCODE Genetics, Amgen, Iceland.

Bastian Hengerer (B)

Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research, Biberach, Germany.

Evangelia Yannaki (E)

Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, George Papanikolaou Hospital, Thessaloniki, Greece; Department of Medicine, University of Washington, Seattle, Washington.

John A Stamatoyannopoulos (JA)

Altius Institute for Biomedical Sciences, Seattle, Washington; Department of Genome Sciences, University of Washington, Seattle, Washington; Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington.

Noa Benaroya-Milshtein (N)

Child and Adolescent Psychiatry Department, Schneider Children's Medical Center of Israel, Petah-Tikva. Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Francesco Cardona (F)

Department of Human Neurosciences, University La Sapienza of Rome, Rome, Italy.

Tammy Hedderly (T)

Evelina London Children's Hospital GSTT, Kings Health Partners AHSC, London, UK.

Isobel Heyman (I)

Psychological Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK.

Chaim Huyser (C)

Levvel Academic Center for Child and Adolescent Psychiatry, Amsterdam, the Netherlands; Amsterdam UMC, Department of Child and Adolescent Psychiatry, Amsterdam, the Netherlands.

Pablo Mir (P)

Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

Astrid Morer (A)

Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; Centro de Investigacion en Red de Salud Mental, Instituto Carlos III, Madrid, Spain.

Norbert Mueller (N)

Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.

Alexander Munchau (A)

Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany.

Kerstin J Plessen (KJ)

Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark; Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.

Cesare Porcelli (C)

ASL BA, Maternal and Childood Department, Adolescence and Childhood Neuropsychiatry Unit, Bari, Italy.

Veit Roessner (V)

Department of Child and Adolescent Psychiatry, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.

Susanne Walitza (S)

Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zürich, Zurich, Switzerland.

Anette Schrag (A)

Department of Clinical Neuroscience, UCL Institute of Neurology, University College London, London, UK.

Davide Martino (D)

Department of Clinical Neurosciences, Cumming School of Medicine & Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Jay A Tischfield (JA)

Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, New Jersey.

Gary A Heiman (GA)

Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, New Jersey.

A Jeremy Willsey (AJ)

Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, California.

Andrea Dietrich (A)

University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, Groningen, the Netherlands.

Lea K Davis (LK)

Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center Nashville, Nashville, Tennessee; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.

James J Crowley (JJ)

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Carol A Mathews (CA)

Department of Psychiatry and Genetics Institute, University of Florida College of Medicine, Gainesville, Florida.

Jeremiah M Scharf (JM)

Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.

Marianthi Georgitsi (M)

1st Laboratory of Medical Biology-Genetics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Pieter J Hoekstra (PJ)

University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, Groningen, the Netherlands. Electronic address: p.hoekstra@accare.nl.

Peristera Paschou (P)

Department of Biological Sciences, Purdue University, West Lafayette, Indiana. Electronic address: ppaschou@purdue.edu.

Classifications MeSH