TitleRare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.
Publication TypeJournal Article
Year of Publication2017
AuthorsHuang AY, Yu D, Davis LK, Sul JHoon, Tsetsos F, Ramensky V, Zelaya I, Ramos EMarisa, Osiecki L, Chen JA, McGrath LM, Illmann C, Sandor P, Barr CL, Grados M, Singer HS, Nöthen MM, Hebebrand J, King RA, Dion Y, Rouleau G, Budman CL, Depienne C, Worbe Y, Hartmann A, Müller-Vahl KR, Stuhrmann M, Aschauer H, Stamenkovic M, Schloegelhofer M, Konstantinidis A, Lyon GJ, McMahon WM, Barta C, Tarnok Z, Nagy P, Batterson JR, Rizzo R, Cath DC, Wolanczyk T, Berlin C, Malaty IA, Okun MS, Woods DW, Rees E, Pato CN, Pato MT, Knowles JA, Posthuma D, Pauls DL, Cox NJ, Neale BM, Freimer NB, Paschou P, Mathews CA, Scharf JM, Coppola G
Corporate AuthorsTourette Syndrome Association International Consortium for Genetics(TSAICG), Gilles de la Tourette Syndrome GWAS Replication Initiative(GGRI)
Date Published2017 Jun 21
KeywordsAdolescent, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, Child, Contactins, DNA Copy Number Variations, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Nerve Tissue Proteins, Odds Ratio, Tourette Syndrome, Young Adult

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

Alternate JournalNeuron
PubMed ID28641109
PubMed Central IDPMC5568251
Grant ListK23 MH085057 / MH / NIMH NIH HHS / United States
U54 HD087101 / HD / NICHD NIH HHS / United States
U01 NS040024 / NS / NINDS NIH HHS / United States
R01 MH096767 / MH / NIMH NIH HHS / United States
P30 NS062691 / NS / NINDS NIH HHS / United States
R01 NS016648 / NS / NINDS NIH HHS / United States
K02 NS085048 / NS / NINDS NIH HHS / United States
R01 NS040024 / NS / NINDS NIH HHS / United States
U01 MH109514 / MH / NIMH NIH HHS / United States