Rare Copy Number Variants found for Tourette Syndrome

June 22, 2017


An international team of researchers, including Danielle Posthuma of the VU & VUMC Amsterdam, identified Rare Copy Number Variants in NRXN1 and CNTN6 that increase the risk for Tourette Syndrome. The findings were published in Neuron, June 21.

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.

Highlights of the study are:
• 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.

Manhattan plot of segmental association test results representing genome-wide corrected p values calculated at each CNV breakpoint. The two genome-wide significant association peaks correspond to deletions at NRXN1 (Pseg = 7.0 * 10-6, Pseg-corr = 1.0 * 10-3) and duplications at CNTN6 (Pseg = 5.4 * 10-5, Pseg-corr = 6.9 * 10-3). Red and blue levels correspond to a genome-wide corrected significance level of 0.01 and 0.05, respectively.

Reference: Huang et al., (2017) Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Neuron, 94(6),1101–1111.e7

Link to the publication