Association of SLITRK1 to Gilles de la Tourette Syndrome

Abstract

Previously the Slit and Trk-like family member 1 (SLITRK1) gene was identified as a candidate gene for Gilles de la Tourette Syndrome (GTS) based on a patient that carried a chromosomal inversion on 13q, as well as the identification of two rare DNA variants in the SLITRK1 gene. Since that report, studies have tested for the two rare variants in GTS and either did not find them, or when found, they did not segregate with the disorder in families, casting doubt on the relationship of this gene to GTS. We tested for these two rare variants and genotyped three polymorphisms that tag the currently identified major haplotypes of this gene in a sample of 154 nuclear families with GTS. In addition, the entire coding region was screened for novel DNA variants. We did not find the two reported rare variants in any of the probands or siblings in these families. We did however find significant evidence for association of a single polymorphism and of haplotypes of the three tagging polymorphisms. These findings provide the first support for the original finding indicating SLITRK1 as a susceptibility gene for GTS and indicate that further study of this gene in GTS is warranted.

Replication of association between a SLITRK1 haplotype and Tourette Syndrome in a large sample of families

“…Applying the transmission test for LD as implemented in Haploview, 18 we found SNPs rs9593835 and rs9546538 to be nominally associated with the disorder, whereas the same three-SNP haplotype as reported by Miranda et al 15 (haplotype TCT) was also over-transmitted in our sample (Table 1). Analysis by individual populations is shown in Supplementary Tables 2 and 3 and does not reveal heterogeneity among populations.…”

“…None of the patients carried any of the variants reported by Abelson et al 2 However, significant associations with SNP rs9593835 as well as two three-marker haplotypes were identified, suggesting, for the first time, that there is a common TS risk factor of low penetrance in linkage disequilibrium (LD) with the associated marker and/or haplotypes. 15 The study concluded that confirmation studies were needed in order to support these preliminary findings.…”

“…14 Undertaking a different approach, a recent study tested for association of the TS phenotype with three common tagging single-nucleotide polymorphisms (SNPs; tSNPs) spanning SLITRK1. 15 The study included 154 nuclear families from Canada, with one or more affected children, with a total of 208 affected children for the association analyses. Patients were ascertained using DSM-III-R criteria.…”

“…Following up on the results of Miranda et al, 15 we studied a large sample of European trios with TS (one individual affected with the disorder and their parents) for the three tSNPs, which were selected using the HapMap CEPH European population as reference for SLITRK1 variation (rs9593835, rs9531520 and rs9546538). It should be noted that SNPs rs9593835 and rs9546538 are in very high LD (r 2 = 0.98, Supplementary Table 1).…”

Genetic animal models of Tourette syndrome: The long and winding road from lab to clinic

“…Several follow-up studies that screened for the observed SLITRK1 genetic changes in TS either failed to find them [39][40][41][42], or when identified, they did not segregate with the disorder in families [43,44], hence clouding the link between SLITRK1 and TS. In this context, the original authors rejected claims of confounding population stratification between cases and controls [45], and recent studies by us and other groups have re-highlighted the significance of the initial findings by demonstrating a strong over-transmission of alleles and/or haplotypes of SLITRK1 to affected individuals [46][47][48]. All in all, there is a consensus that the TS gene discovery story has had a promising start.…”