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

Dongmei Yu; Jae Hoon Sul; Fotis Tsetsos; Muhammad Nawaz; Alden Huang; Ivette Zelaya; Cornelia Illmann; Lisa Osiecki; Sabrina Darrow; Matthew Hirschtritt; Erica Greenberg; Kirsten Muller-Vahl; Manfred Stuhrmann; Yves Dion; Guy Rouleau; Harald Aschauer; Mara Stamenkovic; Monika Schlögelhofer; Paul Sandor; Cathy Barr; Marco Grados; Harvey Singer; Markus Nöthen; Johannes Hebebrand; Anke Hinney; Robert King; Thomas Fernandez; Csaba Barta; Zsanett Tarnok; Peter Nagy; Christel Depienne; Yulia Worbe; Andreas Hartmann; Cathy Budman; Renata Rizzo; Gholson Lyon; William Mcmahon; James Batterson; Danielle Cath; Irene Malaty; Michael Okun; Cheston Berlin; Douglas Woods; Paul Lee; Joseph Jankovic; Mary Robertson; Donald Gilbert; Lawrence Brown; Barbara Coffey; Andrea Dietrich; Pieter Hoekstra; Samuel Kuperman; Samuel Zinner; Pétur Luðvigsson; Evald Sæmundsen; Ólafur Thorarensen; Gil Atzmon; Nir Barzilai; Michael Wagner; Rainald Moessner; Roel Ophoff; Carlos Pato; Michele Pato; James Knowles; Joshua Roffman; Jordan Smoller; Randy Buckner; a Jeremy Willsey; Jay Tischfield; Gary Heiman; Hreinn Stefansson; Kári Stefansson; Danielle Posthuma; Nancy Cox; David Pauls; Nelson Freimer; Benjamin Neale; Lea Davis; Peristera Paschou; Giovanni Coppola; Carol Mathews; Jeremiah Scharf

doi:10.1176/appi.ajp.2018.18070857

Journal Articles The American Journal of Psychiatry Year : 2019

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

(1, 2) , (3, 4) , (5, 6) , (7) , (3, 4) , (3, 4) , (1) , (1) , (4) , (1) , (8) , (8) , (8) , (9) , (10) , (11) , (11) , , (12, 13) , (14) , (15) , (15) , (16) , , , (17) , (17) , (18) , , , (19) , (19, 20) , (19, 20) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

Dongmei Yu

Function : Author

Massachusetts General Hospital [Boston]

Broad Institute of MIT and Harvard

Jae Hoon Sul

Function : Author

David Geffen School of Medicine [Los Angeles]

University of California [Los Angeles]

Fotis Tsetsos

Function : Author

Democritus University of Thrace

Purdue University [West Lafayette]

Muhammad Nawaz

Function : Author

deCODE genetics [Reykjavik]

Alden Huang

Function : Author

David Geffen School of Medicine [Los Angeles]

University of California [Los Angeles]

Ivette Zelaya

Function : Author

David Geffen School of Medicine [Los Angeles]

University of California [Los Angeles]

Cornelia Illmann

Function : Author

Massachusetts General Hospital [Boston]

Lisa Osiecki

Function : Author

Massachusetts General Hospital [Boston]

Sabrina Darrow

Function : Author

University of California [Los Angeles]

Matthew Hirschtritt

Function : Author

Massachusetts General Hospital [Boston]

Erica Greenberg

Function : Author

Medizinische Hochschule Hannover = Hannover Medical School

Kirsten Muller-Vahl

Function : Author

Medizinische Hochschule Hannover = Hannover Medical School

Manfred Stuhrmann

Function : Author

Medizinische Hochschule Hannover = Hannover Medical School

Yves Dion

Function : Author

McGill University Health Center [Montreal]

Guy Rouleau

Function : Author

McGill University = Université McGill [Montréal, Canada]

Harald Aschauer

Function : Author

Medizinische Universität Wien = Medical University of Vienna

Mara Stamenkovic

Function : Author

Medizinische Universität Wien = Medical University of Vienna

Monika Schlögelhofer

Function : Author

Paul Sandor

Function : Author

University Health Network [Toronto, ON, Canada]

University of Toronto

Cathy Barr

Function : Author

Krembil Research Institute

Marco Grados

Function : Author

Johns Hopkins University School of Medicine [Baltimore]

Harvey Singer

Function : Author

Johns Hopkins University School of Medicine [Baltimore]

Markus Nöthen

Function : Author

University Hospital Bonn

Johannes Hebebrand

Function : Author

Anke Hinney

Function : Author

Robert King

Function : Author

Yale School of Medicine [New Haven, Connecticut]

Thomas Fernandez

Function : Author

Yale School of Medicine [New Haven, Connecticut]

Csaba Barta

Function : Author

Semmelweis University [Budapest]

Zsanett Tarnok

Function : Author

Peter Nagy

Function : Author

Christel Depienne

Function : Author

Institut du Cerveau = Paris Brain Institute

Yulia Worbe

Function : Author

Institut du Cerveau = Paris Brain Institute

CHU Pitié-Salpêtrière [AP-HP]

Andreas Hartmann

Function : Author

Institut du Cerveau = Paris Brain Institute

CHU Pitié-Salpêtrière [AP-HP]

Cathy Budman

Function : Author

Renata Rizzo

Function : Author

Gholson Lyon

Function : Author

William Mcmahon

Function : Author

James Batterson

Function : Author

Danielle Cath

Function : Author

Irene Malaty

Function : Author

Michael Okun

Function : Author

Cheston Berlin

Function : Author

Douglas Woods

Function : Author

Paul Lee

Function : Author

Joseph Jankovic

Function : Author

Mary Robertson

Function : Author

Donald Gilbert

Function : Author

Lawrence Brown

Function : Author

Barbara Coffey

Function : Author

Andrea Dietrich

Function : Author

Pieter Hoekstra

Function : Author

Samuel Kuperman

Function : Author

Samuel Zinner

Function : Author

Pétur Luðvigsson

Function : Author

Evald Sæmundsen

Function : Author

Ólafur Thorarensen

Function : Author

Gil Atzmon

Function : Author

Nir Barzilai

Function : Author

Michael Wagner

Function : Author

Rainald Moessner

Function : Author

Roel Ophoff

Function : Author

Carlos Pato

Function : Author

Michele Pato

Function : Author

James Knowles

Function : Author

Joshua Roffman

Function : Author

Jordan Smoller

Function : Author

Randy Buckner

Function : Author

a Jeremy Willsey

Function : Author

Jay Tischfield

Function : Author

Gary Heiman

Function : Author

Hreinn Stefansson

Function : Author

Kári Stefansson

Function : Author

Danielle Posthuma

Function : Author

Nancy Cox

Function : Author

David Pauls

Function : Author

Nelson Freimer

Function : Author

Benjamin Neale

Function : Author

Lea Davis

Function : Author

Peristera Paschou

Function : Author

Giovanni Coppola

Function : Author

Carol Mathews

Function : Author

Jeremiah Scharf

Function : Author

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

Domains

Life Sciences [q-bio]

Gestionnaire HAL 4 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04566192

Submitted on : Thursday, May 2, 2024-2:09:29 PM

Last modification on : Friday, May 3, 2024-3:22:13 AM

Dates and versions

hal-04566192 , version 1 (02-05-2024)

Identifiers

HAL Id : hal-04566192 , version 1
DOI : 10.1176/appi.ajp.2018.18070857
PUBMED : 30818990
PUBMEDCENTRAL : PMC6677250

Cite

Dongmei Yu, Jae Hoon Sul, Fotis Tsetsos, Muhammad Nawaz, Alden Huang, et al.. Interrogating the Genetic Determinants of Tourette’s Syndrome and Other Tic Disorders Through Genome-Wide Association Studies. The American Journal of Psychiatry, 2019, 176 (3), pp.217-227. ⟨10.1176/appi.ajp.2018.18070857⟩. ⟨hal-04566192⟩

Export

BibTeX XML-TEI Dublin Core DC Terms EndNote DataCite

Collections

CNRS ICM SORBONNE-UNIVERSITE SU-MEDECINE

9 View

0 Download

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

Abstract

Keywords

Domains

Dates and versions

Identifiers

Cite

Export

Collections

Altmetric

Share