Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor
Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor
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DOI：
10.1212/wnl.0b013e31825fdeed
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发表时间：
2012-07-01
期刊：
影响因子：
9.9
通讯作者：
Kuhlenbaeumer, Gregor
中科院分区：
文献类型：
--
作者：
Thier, Sandra;Lorenz, Delia;Kuhlenbaeumer, Gregor
目的：散发性、遗传复杂的原发性震颤（ET）是最常见的运动障碍之一，可导致严重的生活质量损害。尽管遗传力高，ET的遗传决定因素在很大程度上是未知的。我们对ET进行了第二次全基因组关联研究（GWAS），以阐明ET的遗传风险因素。方法：使用AffysseTM全基因组SNP阵列6.0（1000 K），我们在来自欧洲的总共990名受试者和1，537名对照受试者中进行了两阶段GWAS，以确定与ET相关的遗传变异。我们在第一阶段样本中发现了主要胶质细胞谷氨酸转运蛋白（SLC 1A 2）基因的内含子变异与ET的相关性（rs3794087，p = 6.95 x 10（-5），比值比[OR] = 1.46）。我们在第二阶段样本中验证了rs3794087与ET的相关性（p = 1.25 x 10（-3），OR = 1.38）。在被归类为明确ET的患者的亚组分析中，rs3794087在合并的第一和第二阶段样本中获得了全基因组显著性（p = 3.44 x 10（-10），OR = 1.59）。利用非同义单核苷酸多态性（SNPs）和与rs3794087高度连锁不平衡的SNPs进行遗传精细定位，未发现任何SNPs与ET的关联性比rs3794087更强。结论：我们确定了编码脑中主要胶质细胞高亲和力谷氨酸再摄取转运蛋白的SLC 1A 2为潜在的ET易感基因。急性和慢性肾上腺素能过度兴奋参与了ET的发病机制。因此，SLC 1A 2是ET的良好功能候选基因。神经病学（R）2012;79：243-248
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 = 6.95 x 10(-5), odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 x 10(-3), OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 x 10(-10), OR = 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(R) 2012;79:243-248