title: Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes.
abstract: BACKGROUND
  Catechol-O-methyltransferase (COMT) has been investigated for its possible role in a wide range of psychiatric phenotypes. In particular, several studies support association of this gene with panic disorder and other anxiety-related traits.
  
  
  METHODS
  We examined the COMT gene for association with genetic risk across a range of anxiety spectrum phenotypes. We used multivariate structural equation modeling to select twin pairs scoring at the extremes of a latent genetic risk factor shared by neuroticism, several anxiety disorders, and major depression from a large population-based twin sample. With one member from each of these pairs, the resulting sample of 589 cases and 539 control subjects were entered into a two-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2.
  
  
  RESULTS
  The functional val158met polymorphism (rs4680) plus nine other single nucleotide polymorphism markers selected to capture the major allelic variation across the COMT locus were analyzed for differences between cases and control subjects. Although the val (G) allele of rs4680 showed marginally significant association in our combined stage 1 plus stage 2 sample, a high-risk haplotype of this allele with the A allele of rs165599 was significantly over-represented in cases (p = 1.97e-5, odds ratio = 1.95). This haplotype also predicted individual differences in neuroticism and risk for several anxiety disorders and major depression. Consistent with prior studies, our findings are female-specific.
  
  
  CONCLUSIONS
  Variations in the COMT gene contribute to genetic risk shared across a range of anxiety-related phenotypes.
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, 23298-0126, USA. jhettema@vcu.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Hettema
authors.forename: Seon-Sook
authors.initials: SS
authors.lastname: An
authors.forename: Jozsef
authors.initials: J
authors.lastname: Bukszar
authors.forename: Edwin J C G
authors.initials: EJ
authors.lastname: van den Oord
authors.forename: Michael C
authors.initials: MC
authors.lastname: Neale
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.forename: Xiangning
authors.initials: X
authors.lastname: Chen
mesh_terms: D000328:Adult; D001008:Anxiety Disorders / Q000453:epidemiology / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D016009:Chi-Square Distribution; D018672:Community Health Planning; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine