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
Essential tremor (ET) is one of the most common movement disorders. Former association studies focussing on candidate genes in ET found a number of risk variants but most of them were not replicated. Recently, a genome-wide association study revealed two intronic sequence variants in the LINGO1 gene associated with ET. Here, we have confirmed association between sequence variants in the LINGO1 gene and the ET phenotype in independent German and French ET samples. The odds ratios for the identified intronic markers rs8030859 (P = 1.0x10(-4)), rs9652490 (P = 9.1x10(-4)), and rs11856808 (P = 3.6x10(-2)) were 1.72 (CI 1.31-2.26), 1.61 (CI 1.21-2.14), and 1.30 (CI 1.02-1.66), respectively, in our German sample. LINGO1 is an interesting candidate gene because it plays a key role in central nervous system biology, is selectively expressed in the nervous system, and is an inhibitor of oligodendrocyte differentiation and neuronal myelination. Our study gives further evidence that LINGO1 acts as a susceptibility gene for ET.
In our samples, no evidence of association between GABA(A) R and GABA transporter genes with ET was detected. Further studies are necessary to clarify the role of these genes in ET.
Essential tremor (ET) and Parkinson's disease (PD) are the most common movement disorders and show clinical, genetic, and pathophysiological overlap. Single-nucleotide polymorphisms (SNPs) in the leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing, Nogo receptor-interacting protein gene (LINGO1) are associated with ET. LINGO1 is overexpressed in the substantia nigra (SN) of PD patients and inhibition of LINGO1 confers neuroprotection in a rodent model of PD. In this study we test the hypothesis whether SNPs in the LINGO1 gene that are associated with ET are also associated with PD. Three large German case-control samples from Kiel, Lübeck, and Tübingen (total: 1,798 cases and 1,482 controls) were genotyped for the three LINGO1 SNPs associated with ET. Association was assessed using allele- and genotype-based tests in each of the three samples separately, in the combined sample, and in subsets of patients with early-onset PD (<50 years) and of patients with a positive family history of PD. Neither of the three samples alone nor the combined sample showed evidence for association between LINGO1 SNPs and PD. The allele-based test showed a trend toward nominal association for all three SNPs in the Kiel sample. The subsets with early-onset PD or a positive family history did also not reveal evidence for association. SNPs in the LINGO1 gene associated with ET could not be shown to be associated with PD in our study population, despite a postulated overlap between both diseases.
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