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

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 discovere...

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Published in:	Neuron (Cambridge, Mass.) Vol. 94; no. 6; p. 1101
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	United States 21.06.2017
Subjects:	Adolescent Adult Calcium-Binding Proteins Case-Control Studies Cell Adhesion Molecules, Neuronal - genetics Child Contactins - genetics DNA Copy Number Variations Female Genetic Predisposition to Disease Genome-Wide Association Study Genotype Humans Male Nerve Tissue Proteins - genetics Neural Cell Adhesion Molecules Odds Ratio Tourette Syndrome - genetics White People - genetics Young Adult structural variation genetics copy number variation CNTN6 NRXN1 Tourette Syndrome tic disorders neurodevelopmental disorders
ISSN:	1097-4199, 1097-4199
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4199 1097-4199
DOI:	10.1016/j.neuron.2017.06.010