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 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. •Rare structural variants contribute significantly to the genetic architecture of TS.•Increased global CNV burden is driven by large, rare, clinically relevant events.•NRXN1 deletions and CNTN6 duplications confer a substantial increase in TS risk. 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.