Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies

Tourette Association of America International Consortium for Genetics, Gilles de la Tourette GWAS Replication Initiative, Tourette International Collaborative Genetics Study, Psychiatric Genomics Consortium Tourette Syndrome Working Group

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)217-227
Number of pages11
JournalAmerican Journal of Psychiatry
Volume176
Issue number3
DOIs
StatePublished - Jan 1 2019

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Tic Disorders
Tourette Syndrome
Genome-Wide Association Study
Tics
Meta-Analysis
Population
Genes
Corpus Striatum
Chromosomes, Human, Pair 13
Prefrontal Cortex
Genome
Gene Expression

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Tourette Association of America International Consortium for Genetics, Gilles de la Tourette GWAS Replication Initiative, Tourette International Collaborative Genetics Study, & Psychiatric Genomics Consortium Tourette Syndrome Working Group (2019). Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies. American Journal of Psychiatry, 176(3), 217-227. https://doi.org/10.1176/appi.ajp.2018.18070857

Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies. / Tourette Association of America International Consortium for Genetics; Gilles de la Tourette GWAS Replication Initiative; Tourette International Collaborative Genetics Study; Psychiatric Genomics Consortium Tourette Syndrome Working Group.

In: American Journal of Psychiatry, Vol. 176, No. 3, 01.01.2019, p. 217-227.

Research output: Contribution to journalArticle

Tourette Association of America International Consortium for Genetics, Gilles de la Tourette GWAS Replication Initiative, Tourette International Collaborative Genetics Study & Psychiatric Genomics Consortium Tourette Syndrome Working Group 2019, 'Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies', American Journal of Psychiatry, vol. 176, no. 3, pp. 217-227. https://doi.org/10.1176/appi.ajp.2018.18070857
Tourette Association of America International Consortium for Genetics, Gilles de la Tourette GWAS Replication Initiative, Tourette International Collaborative Genetics Study, Psychiatric Genomics Consortium Tourette Syndrome Working Group. Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies. American Journal of Psychiatry. 2019 Jan 1;176(3):217-227. https://doi.org/10.1176/appi.ajp.2018.18070857
Tourette Association of America International Consortium for Genetics ; Gilles de la Tourette GWAS Replication Initiative ; Tourette International Collaborative Genetics Study ; Psychiatric Genomics Consortium Tourette Syndrome Working Group. / Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies. In: American Journal of Psychiatry. 2019 ; Vol. 176, No. 3. pp. 217-227.
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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.",
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TY - JOUR

T1 - Interrogating the genetic determinants of Tourette's syndrome and other tiC disorders through genome-wide association studies

AU - Tourette Association of America International Consortium for Genetics

AU - Gilles de la Tourette GWAS Replication Initiative

AU - Tourette International Collaborative Genetics Study

AU - Psychiatric Genomics Consortium Tourette Syndrome Working Group

AU - Yu, Dongmei

AU - Sul, Jae Hoon

AU - Tsetsos, Fotis

AU - Nawaz, Muhammad S.

AU - Huang, Alden Y.

AU - Zelaya, Ivette

AU - Illmann, Cornelia

AU - Osiecki, Lisa

AU - Darrow, Sabrina M.

AU - Hirschtritt, Matthew E.

AU - Greenberg, Erica

AU - Muller-Vahl, Kirsten R.

AU - Stuhrmann, Manfred

AU - Dion, Yves

AU - Rouleau, Guy

AU - Aschauer, Harald

AU - Stamenkovic, Mara

AU - Schlögelhofer, Monika

AU - Sandor, Paul

AU - Barr, Cathy L.

AU - Grados, Marco

AU - Singer, Harvey

AU - Nöthen, Markus M.

AU - Hebebrand, Johannes

AU - Hinney, Anke

AU - King, Robert A.

AU - Fernandez, Thomas V.

AU - Barta, Csaba

AU - Tarnok, Zsanett

AU - Nagy, Peter

AU - Depienne, Christel

AU - Worbe, Yulia

AU - Hartmann, Andreas

AU - Budman, Cathy L.

AU - Rizzo, Renata

AU - Lyon, Gholson J.

AU - McMahon, William M.

AU - Batterson, James R.

AU - Cath, Danielle C.

AU - Malaty, Irene A.

AU - Okun, Michael S.

AU - Berlin, Cheston

AU - Woods, Douglas W.

AU - Lee, Paul C.

AU - Jankovic, Joseph

AU - Robertson, Mary M.

AU - Gilbert, Donald L.

AU - Brown, Lawrence W.

AU - Coffey, Barbara J.

AU - Dietrich, Andrea

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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