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 S Nawaz
Alden Y. Huang
Ivette Zelaya
Cornelia Illmann
Lisa Osiecki
Sabrina M. Darrow
Matthew E. Hirschtritt
Erica Greenberg
Kirsten R. Muller-Vahl
Manfred Stuhrmann
Yves Dion
Guy Rouleau
Harald Aschauer
Mara Stamenkovic
Monika Schlögelhofer
Paul Sandor
Cathy L. Barr
Marco Grados
Harvey S. Singer
Markus M. Nöthen
Johannes Hebebrand
Anke Hinney
Robert A. King
Thomas V. Fernandez
Csaba Barta
Zsanett Tarnok
Peter Nagy
Christel Depienne
Yulia Worbe
Andreas Hartmann
Cathy L. Budman
Renata Rizzo
Gholson J. Lyon
William M. McMahon
James R. Batterson, Children's Mercy HospitalFollow
Danielle C. Cath
Irene A. Malaty
Michael S. Okun
Cheston Berlin
Douglas W. Woods
Paul C. Lee
Joseph Jankovic
Mary M. Robertson
Donald L. Gilbert
Lawrence W. Brown
Barbara J. Coffey
Andrea Dietrich
Pieter J. Hoekstra
Samuel Kuperman
Samuel H. Zinner
Pétur Luðvigsson
Evald Sæmundsen
Ólafur Thorarensen
Gil Atzmon
Nir Barzilai
Michael Wagner
Rainald Moessner
Roel Ophoff
Carlos N. Pato
Michele T. Pato
James A. Knowles
Joshua L. Roffman
Jordan W. Smoller
Randy L. Buckner
A Jeremy Willsey
Jay A. Tischfield
Gary A. Heiman
Hreinn Stefansson
Kári Stefansson
Danielle Posthuma
Nancy J. Cox
David L. Pauls
Nelson B. Freimer
Benjamin M. Neale
Lea K. Davis
Peristera Paschou
Giovanni Coppola
Carol A. Mathews
Jeremiah M. Scharf
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 Group

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DOI: 10.1176/appi.ajp.2018.18070857; PMCID: PMC6677250


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.

Journal Title

The American journal of psychiatry





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MeSH Keywords

Case-Control Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Risk Factors; Severity of Illness Index; Tic Disorders; Tourette Syndrome; fms-Like Tyrosine Kinase 3


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

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