Catechol-O-methyltransferase Contributes to Genetic Susceptibility Shared Among Anxiety Spectrum Phenotypes

Overview

Journal Biol Psychiatry

Publisher Elsevier

Specialty Psychiatry

Date 2008 Apr 26

PMID 18436194

Citations 42

Authors

John M Hettema

Seon-Sook An

Jozsef Bukszar

Edwin J C G van den Oord

Michael C Neale

Kenneth S Kendler

Xiangning Chen

Affiliations

Soon will be listed here.

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.

Citing Articles

The Influence of Genetic Polymorphic Variability of the Catechol-O-methyltransferase Gene in a Group of Patients with a Diagnosis of Behavioural Addiction, including Personality Traits.

Reclaw R, Chmielowiec K, Suchanecka A, Boron A, Chmielowiec J, Stronska-Pluta A Genes (Basel). 2024; 15(3).

PMID: 38540358 PMC: 10969953. DOI: 10.3390/genes15030299.

Investigating the role of the relaxin-3/RXFP3 system in neuropsychiatric disorders and metabolic phenotypes: A candidate gene approach.

Wong W, Arathimos R, Lewis C, Young A, Dawe G PLoS One. 2023; 18(11):e0294045.

PMID: 37967073 PMC: 10651050. DOI: 10.1371/journal.pone.0294045.

Effects of oxycodone pharmacogenetics on postoperative analgesia and related clinical outcomes in children: a pilot prospective study.

Aruldhas B, Quinney S, Packiasabapathy S, Overholser B, Raymond O, Sivam S Pharmacogenomics. 2023; 24(4):187-197.

PMID: 36946298 PMC: 10061242. DOI: 10.2217/pgs-2022-0149.

Catechol-O-Methyltransferase Effects on Smoking: A Review and Proof of Concept of Sex-Sensitive Effects.

DeVito E, Sofuoglu M Curr Behav Neurosci Rep. 2023; 9(4):113-123.

PMID: 36644316 PMC: 9838826. DOI: 10.1007/s40473-022-00251-2.

Association of Neurotensin Receptor 1 Gene Polymorphisms With Defense Mechanisms in Healthy Chinese.

Ma H, Li M, Zhang L, Tao J, Zhu G Front Psychiatry. 2021; 12:762276.

PMID: 34867546 PMC: 8635706. DOI: 10.3389/fpsyt.2021.762276.

References

Domschke K, Deckert J, ODonovan M, Glatt S . Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. Am J Med Genet B Neuropsychiatr Genet. 2007; 144B(5):667-73. DOI: 10.1002/ajmg.b.30494. View

van Gestel S, Houwing-Duistermaat J, Adolfsson R, van Duijn C, Van Broeckhoven C . Power of selective genotyping in genetic association analyses of quantitative traits. Behav Genet. 2000; 30(2):141-6. DOI: 10.1023/a:1001907321955. View

Sullivan P, Neale M, Silverman M, Myakishev M, Wormley B, Webb B . An association study of DRD5 with smoking initiation and progression to nicotine dependence. Am J Med Genet. 2001; 105(3):259-65. DOI: 10.1002/ajmg.1301. View

Hettema J, Neale M, Myers J, Prescott C, Kendler K . A population-based twin study of the relationship between neuroticism and internalizing disorders. Am J Psychiatry. 2006; 163(5):857-64. DOI: 10.1176/ajp.2006.163.5.857. View

Excoffier L, Slatkin M . Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol. 1995; 12(5):921-7. DOI: 10.1093/oxfordjournals.molbev.a040269. View

Bukszar J, van den Oord E . Optimization of two-stage genetic designs where data are combined using an accurate and efficient approximation for Pearson's statistic. Biometrics. 2006; 62(4):1132-7. DOI: 10.1111/j.1541-0420.2006.00583.x. View

Colhoun H, McKeigue P, Davey Smith G . Problems of reporting genetic associations with complex outcomes. Lancet. 2003; 361(9360):865-72. DOI: 10.1016/s0140-6736(03)12715-8. View

Hashimoto R, Noguchi H, Hori H, Ohi K, Yasuda Y, Takeda M . A possible association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and the personality trait of harm avoidance in Japanese healthy subjects. Neurosci Lett. 2007; 428(1):17-20. DOI: 10.1016/j.neulet.2007.09.036. View

Kendler K, Gardner C, Prescott C . Panic syndromes in a population-based sample of male and female twins. Psychol Med. 2001; 31(6):989-1000. DOI: 10.1017/s0033291701004226. View

10.

Dempster E, Mill J, Craig I, Collier D . The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression. BMC Med Genet. 2006; 7:10. PMC: 1456954. DOI: 10.1186/1471-2350-7-10. View

11.

van den Oord E . Controlling false discoveries in candidate gene studies. Mol Psychiatry. 2005; 10(3):230-1. DOI: 10.1038/sj.mp.4001581. View

12.

Bukszar J, van den Oord E . Accurate and efficient power calculations for 2 x m tables in unmatched case-control designs. Stat Med. 2005; 25(15):2632-46. DOI: 10.1002/sim.2269. View

13.

Worda C, Sator M, Schneeberger C, Jantschev T, Ferlitsch K, Huber J . Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reprod. 2003; 18(2):262-6. DOI: 10.1093/humrep/deg059. View

14.

Stein M, Fallin M, Schork N, Gelernter J . COMT polymorphisms and anxiety-related personality traits. Neuropsychopharmacology. 2005; 30(11):2092-102. DOI: 10.1038/sj.npp.1300787. View

15.

Bray N, Buckland P, Williams N, Williams H, Norton N, Owen M . A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet. 2003; 73(1):152-61. PMC: 1180576. DOI: 10.1086/376578. View

16.

DeLisi L, Faraone S . When is a "positive" association truly a "positive" in psychiatric genetics? A commentary based on issues debated at the World Congress of Psychiatric Genetics, Boston, October 12-18, 2005. Am J Med Genet B Neuropsychiatr Genet. 2006; 141B(4):319-22. DOI: 10.1002/ajmg.b.30321. View

17.

Hamilton S, Slager S, Heiman G, Deng Z, Haghighi F, Klein D . Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry. 2002; 51(7):591-601. DOI: 10.1016/s0006-3223(01)01322-1. View

18.

Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N . Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004; 96(6):434-42. PMC: 7713993. DOI: 10.1093/jnci/djh075. View

19.

Enoch M, Xu K, Ferro E, Harris C, Goldman D . Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism. Psychiatr Genet. 2003; 13(1):33-41. DOI: 10.1097/00041444-200303000-00006. View

20.

Kim S, Kim Y, Kim S, Lee H, Kim C . An association study of catechol-O-methyltransferase and monoamine oxidase A polymorphisms and personality traits in Koreans. Neurosci Lett. 2006; 401(1-2):154-8. DOI: 10.1016/j.neulet.2006.03.006. View