Abstract
Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.
Highlights
Tourette syndrome (TS) is a childhood onset neuropsychiatric illness characterised by the occurrence of multiple, motor and vocal tics and is often associated with obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD) [1,2,3,4,5]
Two of the TS cases had two large Copy number variation (CNV) each, while no control carried more than one large CNV
Since no controls were available for the Central Valley of Costa Rica (CVCR) samples, we evaluated the effect of population stratification by testing the correlation of CNV burden with ancestry of the samples, evaluated using Principal component analysis (PCA)
Summary
TS is a childhood onset neuropsychiatric illness characterised by the occurrence of multiple, motor and vocal tics and is often associated with obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD) [1,2,3,4,5]. Twin studies have estimated a sibling relative risk ratio for TS of about 6–8 [2], one of the highest amongst neuropsychiatric disorders. Genome-wide linkage and candidate gene association studies have failed to provide robust evidence implicating specific loci, and a recent GWAS has not identified common variants associated with TS at genome-wide significance thresholds [8]. The observation of chromosomal abnormalities in TS families [9,10,11] has suggested the possibility that genomic rearrangements could play an important role in this disorder, but prior studies have provided conflicting evidence regarding the involvement of copy number variants (CNVs) in TS [12,13]. To further evaluate the role of CNVs in TS, we performed a genomewide study of CNVs in a case/control sample from two well-studied, closely related Latin American population isolates
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