Family-based genetic association study of DLGAP3 in Tourette Syndrome

Abstract

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that is familial and highly heritable. Although genetic influences are thought to play a significant role in the development of TS, no definite TS susceptibility genes have been identified to date. TS is believed to be genetically related to both obsessive-compulsive disorder (OCD) and grooming disorders (GD) such as trichotillomania (TTM). SAP90/PSD95-associated protein 3 (SAPAP3/DLGAP3) is a post-synaptic scaffolding protein that is highly expressed in glutamatergic synapses in the striatum and has recently been investigated as a candidate gene in both OCD and GD studies. Given the shared familial relationship between TS, OCD and TTM, DLGAP3 was evaluated as a candidate TS susceptibility gene. In a family-based sample of 289 TS trios, 22 common single nucleotide polymorphisms (SNPs) in the DLGAP3 region were analyzed. Nominally significant associations were identified between TS and rs11264126 and two haplotypes containing rs11264126 and rs12141243. Secondary analyses demonstrated that these results cannot be explained by the presence of comorbid OCD or TTM in the sample. Although none of these results remained significant after correction for multiple hypothesis testing, DLGAP3 remains a promising candidate gene for TS.

FIGURE 1

Linkage disequilibrium (LD) map and haplotype structure of the DLGAP3 locus. DLGAP3 and the downstream open reading frame C1orf212 are indicated relative to the positions of the 22 genotyped SNPs in the current study. SNP minor allele frequencies were calculated from non-founders. Haplotype blocks, as defined by the confidence interval classification of Gabriel et al., 2002, are indicated in gray boxes with haplotype frequencies in the study population displayed below each haplotype. The nominally significant SNP rs11264126 is highlighted.