1. Interrogating the Genetic Determinants of Tourette’s Syndrome and Other Tic Disorders Through Genome-Wide Association Studies
- Author
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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, and Scharf, Jeremiah M
- Subjects
Mental Health ,Prevention ,Brain Disorders ,Human Genome ,Neurosciences ,Neurodegenerative ,Serious Mental Illness ,Tourette Syndrome ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,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 ,fms-Like Tyrosine Kinase 3 ,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 ,Child Psychiatry ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
ObjectiveTourette'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.MethodsGWAS 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.ResultsGWAS 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.ConclusionsModulation 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.
- Published
- 2019