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

Alden Y. Huang, Dongmei Yu, Lea K. Davis, Jae Hoon Sul, Fotis Tsetsos, Vasily Ramensky, Ivette Zelaya, Eliana Marisa Ramos, Lisa Osiecki, Jason A. Chen, Lauren M. McGrath, Cornelia Illmann, Paul Sandor, Cathy L. Barr, Marco Grados, Harvey S. Singer, Markus M. Nöthen, Johannes Hebebrand, Robert A. King, Yves DionGuy Rouleau, Cathy L. Budman, Christel Depienne, Yulia Worbe, Andreas Hartmann, Kirsten R. Müller-Vahl, Manfred Stuhrmann, Harald Aschauer, Mara Stamenkovic, Monika Schloegelhofer, Anastasios Konstantinidis, Gholson J. Lyon, William M. McMahon, Csaba Barta, Zsanett Tarnok, Peter Nagy, James R. Batterson, Renata Rizzo, Danielle C. Cath, Tomasz Wolanczyk, Cheston Berlin, Irene A. Malaty, Michael S. Okun, Douglas W. Woods, Elliott Rees, Carlos N. Pato, Michele T. Pato, James A. Knowles, Danielle Posthuma, David L. Pauls, The Tourette Syndrome Association International Consortium for Genetics (TSAICG), The Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI), The Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)

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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. Tourette syndrome is highly genetic, but identifying definitive disease susceptibility genes has been challenging. Huang et al. report two genome-wide, significant, recurrent, rare copy-number variants (NRXN1 deletions and CNTN6 duplications), each conferring a substantial increase in TS risk.

Original languageEnglish
Pages (from-to)1101-1111.e7
Issue number6
Publication statusPublished - 21 Jun 2017

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