Genome-wide association study of Tourette's syndrome.
paper
Primary
Public
- Authors
- Scharf, J M; Yu, D; Mathews, C A; Neale, B M; Stewart, S E; Fagerness, J A; Evans, P; Gamazon, E; Edlund, C K; Service, S K; Tikhomirov, A; Osiecki, L; Illmann, C; Pluzhnikov, A; Konkashbaev, A; Davis, L K; Han, B; Crane, J; Moorjani, P; Crenshaw, A T; Parkin, M A; Reus, V I; Lowe, T L; Rangel-Lugo, M; Chouinard, S; Dion, Y; Girard, S; Cath, D C; Smit, J H; King, R A; Fernandez, T V; Leckman, J F; Kidd, K K; Kidd, J R; Pakstis, A J; State, M W; Herrera, L D; Romero, R; Fournier, E; Sandor, P; Barr, C L; Phan, N; Gross-Tsur, V; Benarroch, F; Pollak, Y; Budman, C L; Bruun, R D; Erenberg, G; Naarden, A L; Lee, P C; Weiss, N; Kremeyer, B; BerrΓo, G B; Campbell, D D; Cardona Silgado, J C; Ochoa, W C; Mesa Restrepo, S C; Muller, H; Valencia Duarte, A V; Lyon, G J; Leppert, M; Morgan, J; Weiss, R; Grados, M A; Anderson, K; Davarya, S; Singer, H; Walkup, J; Jankovic, J; Tischfield, J A; Heiman, G A; Gilbert, D L; Hoekstra, P J; Robertson, M M; Kurlan, R; Liu, C; Gibbs, J R; Singleton, A; North American Brain Expression Consortium; Hardy, J; UK Human Brain Expression Database; Strengman, E; Ophoff, R A; Wagner, M; Moessner, R; Mirel, D B; Posthuma, D; Sabatti, C; Eskin, E; Conti, D V; Knowles, J A; Ruiz-Linares, A; Rouleau, G A; Purcell, S; Heutink, P; Oostra, B A; McMahon, W M; Freimer, N B; Cox, N J; Pauls, D L
- Year
- 2013
- Journal
- Molecular psychiatry
- PMID
- 22889924
- DOI
- 10.1038/mp.2012.69
- PMCID
- PMC3605224
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 Γ 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 Γ 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 Γ 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.
Results of the primary meta-analysis from the three European ancestry TS populationsa) Manhattan plot of all genotyped SNPs for 1285 TS cases and 4964 controls from the EU, AJ and FC populations. Grey line indicates the genome-wide significance threshold of 5 Γ10β8. b) Quantile-quantile plot of observed vs. expected -log (p) values from the primary meta-analysis. The 95% confidence interval of expected values is indicated in grey. The genomic control Ξ» value is 0.996.
Enrichment analysis of functional SNPs within the top signals of the primary TS meta-analysisFilled circles indicate the observed count of expression quantitative trait loci (eQTLs) or methylation QTLs (mQTLs) among the top loci (p<1Γ10β3) in the primary European-derived meta-analysis following LD pruning. Empirical p-values indicate the rank of the observed eQTL (or mQTL) count relative to 1000 random sets of allele-frequency matched SNPs drawn from the entire null distribution of LD-pruned SNPs (hatched boxes). a) Lymphoblast cell line eQTLs, p=0.712; b) Cerebellar eQTLs, p=0.077; c) Frontal cortex eQTLs, p=0.045. d) Cerebellar mQTLs, p=0.011.
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