Investigation of SNP rs2060546 Immediately Upstream to NTN4 in a Danish Gilles de la Tourette Syndrome Cohort

Abstract

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC, and IMMP2L have been tentatively associated with GTS (in a small number of patients), the causative genes underlying GTS pathophysiology remain unknown. In a previous genome-wide association study (GWAS) a single nucleotide polymorphism (SNP, rs2060546) near the Netrin-4 (NTN4 - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1.7; p-value = 5.8 × 10-7] thus warranting further investigations. As NTN4 is one of the axon guidance molecules expressed in the central nervous system and it interacts with the encoded proteins of SLIT and WNT genes guiding the growth cone toward its target, it is an attractive candidate susceptibility gene for GTS. In this study we attempted to replicate the association of rs2060546 with GTS by genotyping a Danish cohort of 240 GTS patients and 1006 healthy controls. Our results did not reveal an association (OR = 1.363; p-value = 0.3329) in the Danish cohort alone, which may be due to the small sample size. However, a meta-analysis including the present cohort and a total of 1316 GTS patients and 5023 controls from the GTS GWAS Replication Initiative (GGRI) and the first GTS-GWAS yielded a significant signal (OR = 3.74; p-value = 0.00018) and same direction of effect in the three cohorts. Thus, our study strengthens the evidence of the possible involvement of NTN4 in GTS etiology, suggesting that further studies in even larger samples and functional studies are warranted to investigate the role of this region in GTS pathogenesis.

Trichotillomania is more related to Tourette disorder than to obsessive-compulsive disorder

“…However, some studies on these genes included patients with both TS and OCD. 155,156 Likewise, we did not find any studies on links between TS candidate genes not mentioned above 153,154,157,158 and TTM. Among these studies, some included patients with both TS and OCD.…”

“…SLITRK1 variants are associated with OCD, 150,151 but also with TTM and TS. 90,[151][152][153][154] This gene seems involved in vulnerability for all three of these disorders.…”

Genetic Approaches to Understanding Psychiatric Disease

“…A follow-up study [212] that included 42 of the top candidates from the initial GWAS found a significant association at rs2060546, near the gene that encodes the axon guidance protein netrin 4 (NTN4), which shows strong expression in the striatum. A recent attempt at replicating this association failed [213]; however, a meta-analysis of 3 cohorts showed significance and consistent direction of effect.…”

Computational methods of analysis for gene expression and genomewide variation data

“…The complex genetic architecture of the GTS has not yet been fully elucidated, for a review see [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54]. Several genetic variants have been implicated in the aetiology of GTS.…”