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Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

2017; Cell Press; Volume: 94; Issue: 6 Linguagem: Inglês

10.1016/j.neuron.2017.06.010

1097-4199

Alden Y. Huang, Dongmei Yu, Lea K. Davis, Jae Hoon Sul, Fotis Tsetsos, Vasily Ramensky, Ivette Zelaya, Eliana Marisa Ramos, Lisa Osiecki, Jason Chen, Lauren M. McGrath, Cornelia Illmann, Paul Sandor, Cathy L. Barr, Marco A. Grados, Harvey S. Singer, Markus M. Nöthen, Johannes Hebebrand, Robert A. King, Yves Dion, Guy A. Rouleau, Cathy L. Budman, Christel Depienne, Yulia Worbe, Andreas Hartmann, Kirsten Müller‐Vahl, Manfred Stuhrmann, H.N. Aschauer, M. Stamenković, Monika Schloegelhofer, Anastasios Konstantinidis, Gholson J. Lyon, William M. McMahon, Csaba Barta, Zsanett Tárnok, Péter Nagy, James R. Batterson, Renata Rizzo, Daniëlle C. Cath, Tomasz Wolañczyk, Cheston M. Berlin, Irene A. Malaty, Michael S. Okun, Douglas W. Woods, Elliott Rees, Carlos N. Pato, Michele T. Pato, James A. Knowles, Daniëlle Posthuma, David L. Pauls, Nancy J. Cox, Benjamin M. Neale, Nelson B. Freimer, Peristera Paschou, Carol A. Mathews, Jeremiah M. Scharf, Giovanni Coppola, Ruth D. Bruun, Sylvain Chouinard, Sabrina M. Darrow, Erica Greenberg, Matthew E. Hirschtritt, Roger Kurlan, James F. Leckman, Mary M. Robertson, Johannes H. Smit,

Williams Syndrome Research

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.