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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;
- 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)
Published Web Location
https://doi.org/10.1016/j.neuron.2017.06.010Abstract
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.
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