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 x 10-3) and known, pathogenic CNVs (OR = 3.03
[1.85-5.07], p = 1.5 x 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.
