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.
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: P F Sullivan; M C Neale; M A Silverman; C Harris-Kerr; M V Myakishev; B Wormley; B T Webb; Y Ma; K S Kendler; R E Straub Journal: Am J Med Genet Date: 2001-04-08
Authors: J F Scherrer; W R True; H Xian; M J Lyons; S A Eisen; J Goldberg; N Lin; M T Tsuang Journal: J Affect Disord Date: 2000 Jan-Mar Impact factor: 4.839
Authors: J A Gogos; M Morgan; V Luine; M Santha; S Ogawa; D Pfaff; M Karayiorgou Journal: Proc Natl Acad Sci U S A Date: 1998-08-18 Impact factor: 11.205
Authors: Sergiy Libert; Kelli Pointer; Eric L Bell; Abhirup Das; Dena E Cohen; John M Asara; Karen Kapur; Sven Bergmann; Martin Preisig; Takeshi Otowa; Kenneth S Kendler; Xiangning Chen; John M Hettema; Edwin J van den Oord; Justin P Rubio; Leonard Guarente Journal: Cell Date: 2011-12-08 Impact factor: 41.582
Authors: A S Howe; H N Buttenschøn; A Bani-Fatemi; E Maron; T Otowa; A Erhardt; E B Binder; N O Gregersen; O Mors; D P Woldbye; K Domschke; A Reif; J Shlik; S Kõks; Y Kawamura; A Miyashita; R Kuwano; K Tokunaga; H Tanii; J W Smoller; T Sasaki; D Koszycki; V De Luca Journal: Mol Psychiatry Date: 2015-09-22 Impact factor: 15.992
Authors: Michael J Sulik; Nancy Eisenberg; Tracy L Spinrad; Kathryn Lemery-Chalfant; Gregory Swann; Kassondra M Silva; Mark Reiser; Daryn A Stover; Brian C Verrelli Journal: Dev Psychopathol Date: 2014-08-27
Authors: Vandana Shashi; Timothy D Howard; Matcheri S Keshavan; Jessica Kaczorowski; Margaret N Berry; Kelly Schoch; Edward J Spence; Thomas R Kwapil Journal: Psychiatry Res Date: 2010-05-20 Impact factor: 3.222
Authors: Minyoung Lee; Steven H Aggen; Takeshi Otowa; Enrique Castelao; Martin Preisig; Hans J Grabe; Catharina A Hartman; Albertine J Oldehinkel; Christel M Middeldorp; Henning Tiemeier; John M Hettema Journal: Int J Methods Psychiatr Res Date: 2016-07-15 Impact factor: 4.035
Authors: Jeanne E Savage; Omari McMichael; Eugenia I Gorlin; Jessica R Beadel; Bethany Teachman; Vladimir I Vladimirov; John M Hettema; Roxann Roberson-Nay Journal: Biol Psychol Date: 2015-04-22 Impact factor: 3.251