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Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette Syndrome

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 ORCID:, 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. and Coppola, Giovanni 2017. Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette Syndrome. Neuron 94 (6) , 1101-1111.e7. 10.1016/j.neuron.2017.06.010

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: Tourette Syndrome; tic disorders; neurodevelopmental disorders; genetics; structural variation; copy number variation; NRXN1; CNTN6
Additional Information: Consortium co-authors: The Tourette Syndrome Association International Consortium for Genetics (TSAICG), The Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)
Publisher: Elsevier (Cell Press)
ISSN: 0896-6273
Date of First Compliant Deposit: 7 July 2017
Date of Acceptance: 6 June 2017
Last Modified: 02 Nov 2022 23:49

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