Neurology · 2012
Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor.
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Thier Sandra, Lorenz Delia, Nothnagel Michael, Poremba Caroline, Papengut Frank, Appenzeller Silke, Paschen Steffen, Hofschulte Frank, Hussl Anna-Christina, Hering Sascha, Poewe Werner, Asmus Friedrich, Gasser Thomas, Schöls Ludger, Christensen Kaare, Nebel Almut, Schreiber Stefan, Klebe Stephan, Deuschl Günther, Kuhlenbäumer Gregor
Аннотация
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 × 10(-5), odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10(-3), OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 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.
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 × 10(-5), odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10(-3), OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 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.
Предметные рубрики MeSH
AdolescentAdultAgedAged, 80 and overConfidence IntervalsEssential TremorExcitatory Amino Acid Transporter 2FemaleGene FrequencyGenome-Wide Association StudyGenotypeGermanyGlutamate Plasma Membrane Transport ProteinsHumansLinkage DisequilibriumMaleMiddle AgedPolymorphism, Single NucleotideQuality ControlWhite PeopleYoung Adult