Literature DB >> 30818990

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

Dongmei Yu1, Jae Hoon Sul1, Fotis Tsetsos1, Muhammad S Nawaz1, Alden Y Huang1, Ivette Zelaya1, Cornelia Illmann1, Lisa Osiecki1, Sabrina M Darrow1, Matthew E Hirschtritt1, Erica Greenberg1, Kirsten R Muller-Vahl1, Manfred Stuhrmann1, Yves Dion1, Guy Rouleau1, Harald Aschauer1, Mara Stamenkovic1, Monika Schlögelhofer1, Paul Sandor1, Cathy L Barr1, Marco Grados1, Harvey S Singer1, Markus M Nöthen1, Johannes Hebebrand1, Anke Hinney1, Robert A King1, Thomas V Fernandez1, Csaba Barta1, Zsanett Tarnok1, Peter Nagy1, Christel Depienne1, Yulia Worbe1, Andreas Hartmann1, Cathy L Budman1, Renata Rizzo1, Gholson J Lyon1, William M McMahon1, James R Batterson1, Danielle C Cath1, Irene A Malaty1, Michael S Okun1, Cheston Berlin1, Douglas W Woods1, Paul C Lee1, Joseph Jankovic1, Mary M Robertson1, Donald L Gilbert1, Lawrence W Brown1, Barbara J Coffey1, Andrea Dietrich1, Pieter J Hoekstra1, Samuel Kuperman1, Samuel H Zinner1, Pétur Luðvigsson1, Evald Sæmundsen1, Ólafur Thorarensen1, Gil Atzmon1, Nir Barzilai1, Michael Wagner1, Rainald Moessner1, Roel Ophoff1, Carlos N Pato1, Michele T Pato1, James A Knowles1, Joshua L Roffman1, Jordan W Smoller1, Randy L Buckner1, A Jeremy Willsey1, Jay A Tischfield1, Gary A Heiman1, Hreinn Stefansson1, Kári Stefansson1, Danielle Posthuma1, Nancy J Cox1, David L Pauls1, Nelson B Freimer1, Benjamin M Neale1, Lea K Davis1, Peristera Paschou1, Giovanni Coppola1, Carol A Mathews1, Jeremiah M Scharf1.   

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.

Entities:  

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

Mesh:

Substances:

Year:  2019        PMID: 30818990      PMCID: PMC6677250          DOI: 10.1176/appi.ajp.2018.18070857

Source DB:  PubMed          Journal:  Am J Psychiatry        ISSN: 0002-953X            Impact factor:   18.112


  28 in total

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