Interrogating the Genetic Determinants of Tourette’s Syndrome and Other Tic Disorders Through Genome-Wide Association Studies
Dongmei Yu
(1, 2)
,
Jae Hoon Sul
(3, 4)
,
Fotis Tsetsos
(5, 6)
,
Muhammad Nawaz
(7)
,
Alden Huang
(3, 4)
,
Ivette Zelaya
(3, 4)
,
Cornelia Illmann
(1)
,
Lisa Osiecki
(1)
,
Sabrina Darrow
(4)
,
Matthew Hirschtritt
(1)
,
Erica Greenberg
(8)
,
Kirsten Muller-Vahl
(8)
,
Manfred Stuhrmann
(8)
,
Yves Dion
(9)
,
Guy Rouleau
(10)
,
Harald Aschauer
(11)
,
Mara Stamenkovic
(11)
,
Monika Schlögelhofer
,
Paul Sandor
(12, 13)
,
Cathy Barr
(14)
,
Marco Grados
(15)
,
Harvey Singer
(15)
,
Markus Nöthen
(16)
,
Johannes Hebebrand
,
Anke Hinney
,
Robert King
(17)
,
Thomas Fernandez
(17)
,
Csaba Barta
(18)
,
Zsanett Tarnok
,
Peter Nagy
,
Christel Depienne
(19)
,
Yulia Worbe
(19, 20)
,
Andreas Hartmann
(19, 20)
,
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
1
Massachusetts General Hospital [Boston]
2 BROAD INSTITUTE - Broad Institute of MIT and Harvard
3 David Geffen School of Medicine [Los Angeles]
4 UCLA - University of California [Los Angeles]
5 DUTH - Democritus University of Thrace
6 Purdue University [West Lafayette]
7 deCODE genetics [Reykjavik]
8 MHH - Medizinische Hochschule Hannover = Hannover Medical School
9 MUHC - McGill University Health Center [Montreal]
10 McGill University = Université McGill [Montréal, Canada]
11 Medizinische Universität Wien = Medical University of Vienna
12 University Health Network [Toronto, ON, Canada]
13 University of Toronto
14 Krembil Research Institute
15 Johns Hopkins University School of Medicine [Baltimore]
16 University Hospital Bonn
17 YSM - Yale School of Medicine [New Haven, Connecticut]
18 Semmelweis University [Budapest]
19 ICM - Institut du Cerveau = Paris Brain Institute
20 CHU Pitié-Salpêtrière [AP-HP]
2 BROAD INSTITUTE - Broad Institute of MIT and Harvard
3 David Geffen School of Medicine [Los Angeles]
4 UCLA - University of California [Los Angeles]
5 DUTH - Democritus University of Thrace
6 Purdue University [West Lafayette]
7 deCODE genetics [Reykjavik]
8 MHH - Medizinische Hochschule Hannover = Hannover Medical School
9 MUHC - McGill University Health Center [Montreal]
10 McGill University = Université McGill [Montréal, Canada]
11 Medizinische Universität Wien = Medical University of Vienna
12 University Health Network [Toronto, ON, Canada]
13 University of Toronto
14 Krembil Research Institute
15 Johns Hopkins University School of Medicine [Baltimore]
16 University Hospital Bonn
17 YSM - Yale School of Medicine [New Haven, Connecticut]
18 Semmelweis University [Budapest]
19 ICM - Institut du Cerveau = Paris Brain Institute
20 CHU Pitié-Salpêtrière [AP-HP]
Monika Schlögelhofer
- Fonction : Auteur
Johannes Hebebrand
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Anke Hinney
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Zsanett Tarnok
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Peter Nagy
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Cathy Budman
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Renata Rizzo
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Gholson Lyon
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William Mcmahon
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James Batterson
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Danielle Cath
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Irene Malaty
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Michael Okun
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Cheston Berlin
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Douglas Woods
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Paul Lee
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Joseph Jankovic
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Mary Robertson
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Donald Gilbert
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Lawrence Brown
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Barbara Coffey
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Andrea Dietrich
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Pieter Hoekstra
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Samuel Kuperman
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Samuel Zinner
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Pétur Luðvigsson
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Evald Sæmundsen
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Ólafur Thorarensen
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Gil Atzmon
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Nir Barzilai
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Michael Wagner
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Rainald Moessner
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Roel Ophoff
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Carlos Pato
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Michele Pato
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James Knowles
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Joshua Roffman
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Jordan Smoller
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Randy Buckner
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a Jeremy Willsey
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Jay Tischfield
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Gary Heiman
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Hreinn Stefansson
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Kári Stefansson
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Danielle Posthuma
- Fonction : Auteur
Nancy Cox
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David Pauls
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Nelson Freimer
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Benjamin Neale
- Fonction : Auteur
Lea Davis
- Fonction : Auteur
Peristera Paschou
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Giovanni Coppola
- Fonction : Auteur
Carol Mathews
- Fonction : Auteur
Jeremiah Scharf
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Résumé
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.