Genome-Wide Association Study of Gilles de la Tourette Syndrome (IN10-1.002) (2012)

Objective: To identify common genetic variants associated with Gilles de la Tourette Syndrome (GTS). Background GTS is a highly heritable, neurodevelopmental disorder, though discovery of definitive GTS susceptibility genes has been challenging. Here, we report the first genome-wide association study (GWAS) of GTS in 1496 cases and 5249 unselected, ancestry-matched controls. Design/Methods: A multi-center case-control study was conducted with subjects of general European ancestry (EU), two European-derived population isolates, Ashkenazi Jews (AJ) and French Canadians (FC), and two closely-related Latin American population isolates from Antioquia, Colombia (ANT) and the Central Valley of Costa Rica (CVCR). Diagnoses were made using DSM-IV-TR criteria. 908 EU cases, all population-isolate cases, 298 EU controls and all FC and ANT controls were genotyped on the Illumina Hap610 platform. An additional 148 EU cases were genotyped on the IlluminaHap370, and remaining EU and AJ controls were previously genotyped on Illumina Hap550K and Hap1M arrays. Quality control (QC) was conducted in PLINK with specific focus on removing SNPs with differential performance across genotyping platforms. Ancestry-stratified case-control analyses were performed in PLINK using logistic regression. Case-weighted meta-analyses were conducted in METAL. Results: and Conclusions: In the primary meta-analysis of European-derived samples (EU, AJ, FC), no loci surpassed the threshold for genome-wide significance (p -8 ). However, the top 535 loci (p COL27A1 gene on chromosome 9 (rs7868992) with a genome-wide significant p-value =2.9 x 10 -8 . Additional neurodevelopmental genes of interest among the top signals included SLITRK6 , CNTN1 , and SEMA3G . Conclusions: Replication in additional samples is underway to validate the findings and to identify additional GTS susceptibility loci. Supported by: A grant from the Judah Foundation, NIH grants NS40024 to DLP and the Tourette Syndrome Association International Consortium for Genetics, NIH grant NS16648 and a grant from the Tourette Syndrome Association to DLP, NIH grant NS037484 to NBF, NIH grant NS043538 to AR-L, and an American Academy of Neurology Foundation grant and NIH grant MH085057 to JMS. Disclosure: Dr. Scharf has nothing to disclose. Dr. Yu has nothing to disclose. Dr. Mathews has nothing to disclose. Dr. Neale has nothing to disclose. Dr. Stewart has nothing to disclose. Dr. Fagerness has nothing to disclose. Dr. Scharf has nothing to disclose. Dr. Scharf has nothing to disclose. Dr. Scharf has nothing to disclose. Dr. Osiecki has nothing to disclose. Dr. Illmann has nothing to disclose. Dr. Cath has nothing to disclose. Dr. King has nothing to disclose. Dr. Dion has received personal compensation for activities with Biovail Pharma, Pfizer and Eli Lilly. Dr. Sandor has received personal compensation for activities with Psyadon, Shire, Solway, UCB Pharma, Janssen, Eli Lilly, Pfizer, and Prestwick. Dr. Barr has nothing to disclose. Dr. Budman has received research support from Psyadon Pharmaceuticals and Otsuka Pharmaceuticals. Dr. Lyon has nothing to disclose. Dr. Hoekstra has received personal compensation for activities with Desitin, Eli Lilly & Company and Shire. Dr. Singer has nothing to disclose. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc. Dr. Gilbert has received personal compensation in an editorial capacity for Pediatrics Review and Education Program R11. Dr. Gilbert has received research support from Psyadon Pharmaceuticals and Otsuka Pharmaceuticals. Dr. Hoekstra has received personal compensation for activities with Desitin, Eli Lilly & Company and Shire. Dr. Heiman has nothing to disclose. Dr. Tischfield has nothing to disclose. Dr. State has nothing to disclose. Dr. Robertson has nothing to disclose. Dr. Kurlan has nothing to disclose. Dr. Ophoff has nothing to disclose. Dr. Gibbs has nothing to disclose. Dr. Cookson has nothing to disclose. Dr. Hardy has nothing to disclose. Dr. Singleton has nothing to disclose. Dr. Rodriguez has nothing to disclose. Dr. Rouleau has nothing to disclose. Dr. Heutink has nothing to disclose. Dr. Oostra has nothing to disclose. Dr. McMahon has nothing to disclose. Dr. Freimer has nothing to disclose. Dr. COX has nothing to disclose. Dr. Pauls has nothing to disclose.