Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Abstract

Objective: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET. Methods:Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET. Results:We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p ϭ 6.95 ϫ 10 Ϫ5 , odds ratio [OR] ϭ 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p ϭ 1.25 ϫ 10 Ϫ3 , OR ϭ 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087obtained genome-wide significance (p ϭ 3.44 ϫ 10 Ϫ10 , OR ϭ 1.59) in the combined first-and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087. Conclusions:We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET. Neurology Sporadic, genetically complex essential tremor (ET) is one of the most frequent neurologic disorders with a prevalence between 0.9% and 4.6% in the population older than 65 years. 1The clinical hallmark of the disease is a postural or kinetic tremor of the upper extremities. Severe ET not only causes permanent disability but often also social stigmatization. In a large proportion of patients, ET can be acutely alleviated by moderate doses of ethanol. 2,3 The diagnosis of ET is based on the clinical examination because no biomarker or specific diagnostic test exists. The most stringent research diagnostic criteria for ET are the consensus criteria proposed by the Tremor Investigation Group (TRIG).1 Family history studies and twin studies demonstrated high heritability with concordance rates of up to 95% in monozygotic vs 29% in

No association of the SLC1A2 rs3794087 allele with risk for essential tremor in the Spanish population

“…The frequency of the rs3794087 variant allele observed in control individuals of this study (25.0%) is almost identical to that reported by Thier et al [10] (22.1%). However, we did not observe an increase in the frequency of the rs3794087 allele among ET patients of the study by Thier et al (31.1%) [10], but a slight nonsignificant decrease in the frequency of the variant allele (21.5%; Table 1).…”

“…However, we did not observe an increase in the frequency of the rs3794087 allele among ET patients of the study by Thier et al (31.1%) [10], but a slight nonsignificant decrease in the frequency of the variant allele (21.5%; Table 1). As we found in the current study, the analysis of the minor allele frequency of rs3794087 by Tan et al [11] showed a nonsignificant trend toward a decreased risk for ET ( Table 2).…”

“…Comparison of the pooled data of the present study with that of the two previous reports [10,11] showed a significant association of the rs3794087T allelic variant with increased risk for ET. However, the interpretation of this result is difficult because of the high level of heterogeneity between these three series.…”

“…A recent genome-wide association study including 658 patients with definite ET and 1490 controls from Germany, Austria, and Denmark found that the rs3794087 single nucleotide polymorphism (SNP) in the SLC1A2 gene was associated with the risk for developing ET, with an odds ratio (OR) and 95% confidence interval of 1.59 (1.36-1.84) [10]. In contrast, a replication study in an Asian cohort including 357 ET patients and 1935 controls showed a decreased risk for ET associated with the rs3794087T allele, with an OR (95% CI) of 0.75 (0.60-0.94) [11].…”

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

“…No clearly causal mutations have been identified in these regions, although the common variant DRD3 p.S9G in the ETM1 region has been proposed as a risk factor and HS1BP3 p.A265G in the ETM2 region appeared in two multiply affected families (6,7). Genomewide association studies of essential tremor reported associations with common variants in an intron of LINGO1 and in an intron of SLC1A2 (8)(9)(10). Recently, DNAJC13 p.N855S, which had been identified in Parkinson disease patients, was also found in two unrelated patients with essential tremor (11).…”