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Genome-wide association study of Tourette's syndrome.

ABSTRACT: Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

SUBMITTER: Scharf JM

PROVIDER: S-EPMC3605224 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association study of Tourette's syndrome.

Scharf J M JM Yu D D Mathews C A CA Neale B M BM Stewart S E SE Fagerness J A JA Evans P P Gamazon E E Edlund C K CK Service S K SK Tikhomirov A A Osiecki L L Illmann C C Pluzhnikov A A Konkashbaev A A Davis L K LK Han B B Crane J J Moorjani P P Crenshaw A T AT Parkin M A MA Reus V I VI Lowe T L TL Rangel-Lugo M M Chouinard S S Dion Y Y Girard S S Cath D C DC Smit J H JH King R A RA Fernandez T V TV Leckman J F JF Kidd K K KK Kidd J R JR Pakstis A J AJ State M W MW Herrera L D LD Romero R R Fournier E E Sandor P P Barr C L CL Phan N N Gross-Tsur V V Benarroch F F Pollak Y Y Budman C L CL Bruun R D RD Erenberg G G Naarden A L AL Lee P C PC Weiss N N Kremeyer B B Berrío G B GB Campbell D D DD Cardona Silgado J C JC Ochoa W C WC Mesa Restrepo S C SC Muller H H Valencia Duarte A V AV Lyon G J GJ Leppert M M Morgan J J Weiss R R Grados M A MA Anderson K K Davarya S S Singer H H Walkup J J Jankovic J J Tischfield J A JA Heiman G A GA Gilbert D L DL Hoekstra P J PJ Robertson M M MM Kurlan R R Liu C C Gibbs J R JR Singleton A A Hardy J J Strengman E E Ophoff R A RA Wagner M M Moessner R R Mirel D B DB Posthuma D D Sabatti C C Eskin E E Conti D V DV Knowles J A JA Ruiz-Linares A A Rouleau G A GA Purcell S S Heutink P P Oostra B A BA McMahon W M WM Freimer N B NB Cox N J NJ Pauls D L DL

Molecular psychiatry 20120814 6

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Cana ...[more]

PMID: 22889924

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Project description: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.

Project description:OBJECTIVE:Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. METHOD:The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. RESULTS:Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). CONCLUSIONS:Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

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Genome-wide association study of Tourette's syndrome.

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Genome-wide association study of Tourette's syndrome.

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