title: 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 = 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.
authors: Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Sandra
authors: S
authors: Thier
authors: Delia
authors: D
authors: Lorenz
authors: Michael
authors: M
authors: Nothnagel
authors: Caroline
authors: C
authors: Poremba
authors: Frank
authors: F
authors: Papengut
authors: Silke
authors: S
authors: Appenzeller
authors: Steffen
authors: S
authors: Paschen
authors: Frank
authors: F
authors: Hofschulte
authors: Anna-Christina
authors: AC
authors: Hussl
authors: Sascha
authors: S
authors: Hering
authors: Werner
authors: W
authors: Poewe
authors: Friedrich
authors: F
authors: Asmus
authors: Thomas
authors: T
authors: Gasser
authors: Ludger
authors: L
authors: Schöls
authors: Kaare
authors: K
authors: Christensen
authors: Almut
authors: A
authors: Nebel
authors: Stefan
authors: S
authors: Schreiber
authors: Stephan
authors: S
authors: Klebe
authors: Günther
authors: G
authors: Deuschl
authors: Gregor
authors: G
authors: Kuhlenbäumer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016001:Confidence Intervals; D020329:Essential Tremor / Q000235:genetics*; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D044465:White People; D055815:Young Adult
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human