title: Accurate, Large-Scale Genotyping of 5HTTLPR and Flanking Single Nucleotide Polymorphisms in an Association Study of Depression, Anxiety, and Personality Measures.
abstract: BACKGROUND
  The length polymorphism repeat in the promoter region of the serotonin transporter gene (5HTTLPR) is one of the most studied polymorphisms for association with a range of psychiatric and personality phenotypes. However, the original 5HTTLPR assay is prone to bias toward short allele calling.
  
  
  METHODS
  We designed new assays for the 5HTTLPR suitable for large-scale genotyping projects and we genotyped 13 single nucleotide polymorphisms (SNPs) in a 38-kilobase region around the 5HTTLPR, including SNP rs25531, a polymorphism of the 5HTTLPR long allele. Association analysis was conducted for major depression and/or anxiety disorder in unrelated cases (n = 1161) and control subjects (n = 1051) identified through psychiatric interviews administered to a large population sample of Australian twin families. Participants had been scored for personality traits several years earlier (n > or = 2643 unrelated individuals).
  
  
  RESULTS
  We identified a two-SNP haplotype proxy for 5HTTLPR; the CA haplotype of SNPs rs4251417 and rs2020934 is coupled with the short allele of 5HTTLPR (r(2) = .72). We found evidence for association (p = .0062, after accounting for multiple testing) for SLC6A4 SNPs rs6354 and rs2020936 (positioned in a different linkage disequilibrium [LD] block about 15.5 kb from 5HTTLPR) with anxiety and/or depression and neuroticism, with the strongest association for recurrent depression with onset in young adulthood (odds ratio = 1.55, 95% confidence interval = 1.16-2.06).
  
  
  CONCLUSIONS
  The associated SNPs are in the same LD block as the variable number of tandem repeats serotonin transporter intron 2 marker, for which association has previously been reported.
authors.affiliation: Genetic and Molecular Epidemiology Laboratories, Queensland Institute of Medical Research, 300 Herston Road, Brisbane 4006, Australia. naomi.wray@qimr.edu.au.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.forename: Michael R
authors.initials: MR
authors.lastname: James
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gordon
authors.forename: Troy
authors.initials: T
authors.lastname: Dumenil
authors.forename: Leanne
authors.initials: L
authors.lastname: Ryan
authors.forename: William L
authors.initials: WL
authors.lastname: Coventry
authors.forename: Dixie J
authors.initials: DJ
authors.lastname: Statham
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
mesh_terms: D000328:Adult; D001008:Anxiety Disorders / Q000235:genetics*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008957:Models, Genetic; D010551:Personality / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins