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.
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, Marcus M.; Hebebrand, Johannes; King, Robert A.; Dion, Yves; Rouleau, Guy; Budman, Cathy L.; Depienne, Christel; Worbe, Yulia; Hartmenn, 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.; and Coppola, Giovanni, "Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome" (2017). Psychology Faculty Research and Publications. 288.
Accepted version. Neuron, Vol. 94, No. 6 (June 21, 2017): 1101-1111. DOI. © 2017 Elsevier B.V. Used with permission.