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. 2017 Jun 21;94(6):1101-1111.e7.
doi: 10.1016/j.neuron.2017.06.010.

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

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Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

Alden Y Huang et al. Neuron. .
Free PMC article


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.

Keywords: CNTN6; NRXN1; Tourette Syndrome; copy number variation; genetics; neurodevelopmental disorders; structural variation; tic disorders.


Figure 1
Figure 1. Flow chart of experimental procedures and analyses
CNVs were called from genome-wide SNP genotype data generated from 2,434 TS cases and 4,093 controls (grey). Data processing, CNV detection and quality control steps (blue) are described in the STAR Methods. An outline of the main analyses is presented in red. Figures or tables relevant to each outlined step are shown in parentheses.
Figure 2
Figure 2. Rare CNV burden in 2,434 TS cases and 4,093 controls
(A) The global burden of all rare (<1% frequency) CNVs > 30kb is shown for genic (top) and non-genic (bottom) CNVs and stratified by CNV type (all, loss (deletions), gain (duplications)). Global CNV burden is compared using three different metrics: CNV count, total number of CNVs per subject; CNV length, aggregate length of all CNVs (in Mb); and CNV gene count, number of genes spanned by CNVs. Control rate, averaged baseline burden metric per control subject. Red boxes, odds ratios (box size is proportional to standard error); Blue lines indicate 95% confidence intervals. Genic CNVs are defined as those that overlap any exon of a known protein-coding gene (see STAR Methods). (B) Analyses in (A) were assessed further by partitioning CNV length burden of all CNVs (deletions + duplications) into different CNV size categories. Whiskers represent 95% confidence intervals. (C) The analysis in (B) was repeated for CNVs binned by frequency. Odds ratios (OR) were calculated from logistic regression adjusted for covariates using standardized burden metrics (STAR Methods). ORs >1 indicate an increased TS risk.
Figure 3
Figure 3. Large, singleton CNVs and known pathogenic variants are overrepresented in TS
(A) CNV count burden restricted to genic singleton events, stratified by CNV size and type (deletion/duplication). (B) CNV burden of all rare CNVs, separated by clinical relevance (benign, uncertain, pathogenic) according to the American College of Medical Genetics guidelines (STAR Methods). Red boxes, odds ratios; Blue lines, 95% CIs. ORs > 1 represent an increase in risk for TS per CNV.
Figure 4
Figure 4. Segmental and gene-based tests converge on two distinct loci significantly enriched in TS cases
(A) 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 (Plocus=7.0×10−6, Pcorr=1.0×10−3) and duplications at CNTN6 (Plocus=5.4×10−5, Pcorr =6.9×10−3). Red and blue levels correspond to a genome-wide corrected α of 0.05 and 0.01, respectively. (B) Heterozygous exonic deletions in NRXN1 found in 12 cases (0.49%) and 1 control (0.03%), corresponding to an OR=20.2, 95% CI (2.6–155.2). Exon-affecting CNVs cluster at the 5′ end with deletions across exons 1–3 found in 10 cases and no controls. Red, deletions in TS cases; Dark Red, deletion in controls; Blue, case duplication. (C) Exon-spanning duplications over CNTN6 found in 12 cases and 2 controls (OR=10.2, [2.0–17.8]) CNTN6 duplications are considerably larger in cases compared to controls (640 vs. 143 kb, on average). Blue, case duplications; Dark blue, control duplications; Red, case deletion; Dark red, control duplication.

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