학술논문
Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.
Document Type
article
Author
Huang, Alden Y; Yu, Dongmei; Davis, Lea K; Sul, Jae Hoon; Tsetsos, Fotis; Ramensky, Vasily; Zelaya, Ivette; Ramos, Eliana Marisa; Osiecki, Lisa; Chen, Jason A; McGrath, Lauren M; Illmann, Cornelia; Sandor, Paul; Barr, Cathy L; Grados, Marco; Singer, Harvey S; Nöthen, Markus M; Hebebrand, Johannes; King, Robert A; Dion, Yves; Rouleau, Guy; Budman, Cathy L; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Müller-Vahl, Kirsten R; Stuhrmann, Manfred; Aschauer, Harald; Stamenkovic, Mara; Schloegelhofer, Monika; Konstantinidis, Anastasios; Lyon, Gholson J; McMahon, William M; Barta, Csaba; Tarnok, Zsanett; Nagy, Peter; Batterson, James R; Rizzo, Renata; Cath, Danielle C; Wolanczyk, Tomasz; Berlin, Cheston; Malaty, Irene A; Okun, Michael S; Woods, Douglas W; Rees, Elliott; Pato, Carlos N; Pato, Michele T; Knowles, James A; Posthuma, Danielle; Pauls, David L; Cox, Nancy J; Neale, Benjamin M; Freimer, Nelson B; Paschou, Peristera; Mathews, Carol A; Scharf, Jeremiah M; Coppola, Giovanni; Tourette Syndrome Association International Consortium for Genetics (TSAICG); Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)
Source
Neuron. 94(6)
Subject
Language
Abstract
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 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). 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.