Matthew W Halvorsen, Sheng Wang, Tyne W Miller-Fleming, Dongmei Yu, Apostolia Topaloudi, Elles de Schipper, Julia Bäckman, David Mataix-Cols, Christian Rück, Behrang Mahjani, Joseph D Buxbaum, Dorothy E Grice, Larisa H Cavallari, Dominick J Angiolillo, Francesco Franchi, Lea K Davis, Lide Han, Douglas M Ruderfer, Psychiatric Genomics Consortium OCD-TS Working Group (PGC-OCD-TS), TS-EUROTRAIN, EMTICS, Tourette International Collaborative Genetics (TIC Genetics), Tourette Association of America International Consortium of Genetics (TAAICG), Nordic OCD and Related Disorders Consortium (NORDIC), Andrea Dietrich, Pieter J Hoekstra, Manuel Mattheisen, Luz M Porras, Paola Giusti-Rodriguez, Carol A Mathews, Peristera Paschou, Jeremiah M Scharf, A Jeremy Willsey, James J Crowley
Tourette Syndrome (TS) and Persistent Tic Disorder (PTD) are childhood-onset neuropsychiatric conditions with high heritability. Due to current sample size limitations, identifying TS/PTD risk genes has been challenging. This study addressed this issue by conducting a meta-analysis of microarray copy number variant (CNV) studies from three TS/PTD genomics consortia, supplemented with new data from 3291 cases. This approach more than doubled the sample size of previous TS/PTD CNV studies, with CNV calls generated from 5725 TS/PTD cases and 10,982 matched controls. The results confirmed that TS/PTD cases 1) have a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes (OR = 1.68, P = 9.3×10-5) and 2) are more likely to carry established neurodevelopmental CNVs (OR = 1.42, P = 3.9×10-2) compared to controls. Additionally, a novel, genome-wide significant CNV locus for TS/PTD was discovered, involving duplications at 17q12 (hg19 chr17:34.8 - 36.2 Mb). This locus is associated with a known duplication syndrome associated with variable neuropsychiatric traits, but has not been previously linked to tic disorders. Eight cases and one control carried the canonical ~1.4 Mb duplication at chr17:34.8-36.2 Mb, while one additional case had a smaller 110 kb duplication within this known CNV that included only one gene, ACACA (acetyl-CoA carboxylase, OR = 26.7, P = 5.69×10-7). Overall, this study provides further evidence that rare, genic CNVs play a substantial role in the genetic architecture of TS/PTD and identifies a new genome-wide significant association with this neurodevelopmental disorder.