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