Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies

Abstract

There is strong evidence for a genetic contribution to schizophrenia, but the contribution of individual candidate genes remains uncertain. We attempted to replicate a recent meta-analysis that reported an association of the catechol O-methyltransferase (COMT) Val allele with schizophrenia, and suggested that this effect may be moderated by ancestry. We included reports published subsequent to the original meta-analysis, and included a formal test of the moderating effect of ancestry in order to test whether the association operates differently in populations of European ancestry compared to populations of Asian ancestry. A corrected P-value for the 5% significance threshold was employed where appropriate, using Bonferroni's method, and studies that demonstrated departure from Hardy–Weinberg equilibrium among controls were excluded. When all studies were included in a meta-regression, there was evidence for a significant association of COMT Val allele frequency with schizophrenia case status and a significant main effect of ancestry. The interaction of COMT Val allele frequency and ancestry was also significant. However, when only studies that reported allele frequencies that did not depart significantly from Hardy–Weinberg equilibrium among controls were included, these effects were no longer significant. The results of our meta-analysis do not support an association between the COMT Val allele and schizophrenia case status, and do not support recent claims that this association may be moderated by ancestry.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Sullivan PF, Kendler KS, Neale MC . Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192.

    Article  Google Scholar 

  2. Cardno AG, Gottesman II . Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 2000; 97: 1217.

    Article  Google Scholar 

  3. Carlsson A . The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1998; 1: 179–186.

    Article  Google Scholar 

  4. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski C, Weinshilboum R . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243–250.

    Article  CAS  Google Scholar 

  5. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melén K, Julkunen I et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202–4210.

    Article  CAS  Google Scholar 

  6. Glatt SJ, Faraone SV, Tsuang MT . Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case–control and family-based studies. Am J Psychiatry 2003; 160: 469–476.

    Article  Google Scholar 

  7. Pittelli SJ . Genetic linkage for schizophrenia? Am J Psychiatry 2004; 161: 1134.

    Article  Google Scholar 

  8. Daniels JK, Williams NM, Williams J, Jones LA, Cardno AG, Murphy KC et al. No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity. Am J Psychiatry 1996; 153: 268–270.

    Article  CAS  Google Scholar 

  9. Strous RD, Bark N, Woerner M, Lachman HM . Lack of association of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia. Biol Psychiatry 1997; 41: 493–495.

    Article  CAS  Google Scholar 

  10. Karayiorgou M, Gogos JA, Galke BL, Wolyniec PS, Nestadt G, Antonarakis SE et al. Identification of sequence variants and analysis of the role of the catechol O-methyl-transferase gene in schizophrenia susceptibility. Biol Psychiatry 1998; 43: 425–431.

    Article  CAS  Google Scholar 

  11. Ohmori O, Shinkai T, Kojima H, Terao T, Suzuki T, Mita T et al. Association study of a functional catechol O-methyltransferase gene polymorphism in Japanese schizophrenics. Neurosci Lett 1998; 243: 109–112.

    Article  CAS  Google Scholar 

  12. de Chaldee M, Laurent C, Thibaut F, Martinez M, Samolyk D, Petit M et al. Linkage disequilibrium on the COMT gene in French schizophrenics and controls. Am J Med Genet 1999; 88: 452–457.

    Article  CAS  Google Scholar 

  13. Chen CH, Lee YR, Chung MY, Wei FC, Koong FJ, Shaw CK et al. Systematic mutation analysis of the catechol O-methyltransferase gene as a candidate gene for schizophrenia. Am J Psychiatry 1999; 156: 1273–1275.

    CAS  PubMed  Google Scholar 

  14. Kotler M, Barak P, Cohen H, Averbuch IE, Grinshpoon A, Gritsenko I et al. Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity. Am J Med Genet 1999; 88: 628–633.

    Article  CAS  Google Scholar 

  15. Egan MF, Goldber TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  Google Scholar 

  16. Arinami T, Ohtsuki T, Takase K, Shimizu H, Yoshikawa T, Horigome H et al. Screening for 22q11 deletions in a schizophrenia population. Schizophr Res 2001; 52: 167–170.

    Article  CAS  Google Scholar 

  17. Herken H, Erdal ME . Catechol O-methyltransferase gene polymorphism in schizophrenia: evidence for association between symptomatology and prognosis. Psychiatr Genet 2001; 11: 105–109.

    Article  CAS  Google Scholar 

  18. Liou YJ, Tsai SJ, Hong CJ, Wang YC, Lai IC . Association analysis of a functional catechol O-methyltransferase gene polymorphism in schizophrenic patients in Taiwan. Neuropsychobiology 2001; 43: 11–14.

    Article  CAS  Google Scholar 

  19. Joober R, Gauthier J, Lal S, Bloom D, Lalonde P, Rouleau G et al. Catechol O-methyltransferase Val-108/158-Met gene variants associated with performance on the Wisconsin Card Sorting Test. Arch Gen Psychiatry 2002; 59: 662–663.

    Article  Google Scholar 

  20. Norton N, Kirov G, Zammit S, Jones G, Jones S, Owen R et al. Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. Am J Med Genet 2002; 114: 491–496.

    Article  Google Scholar 

  21. Park TW, Yoon KS, Kim JH, Park WY, Hirvonen A, Kang D . Functional catechol O-methyltransferase gene polymorphism and susceptibility to schizophrenia. Eur Neuropsychopharmacol 2002; 12: 99–103.

    Article  Google Scholar 

  22. Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002; 71: 1296–1302.

    Article  CAS  Google Scholar 

  23. Inada T, Nakamura A, Iijima Y . Relationship between catechol O-methyltransferase polymorphism and treatment-resistant schizophrenia. Am J Med Genet 2003; 120B: 35–39.

    Article  Google Scholar 

  24. Kremer I, Pinto M, Murad I, Muhaheed M, Bannoura I, Muller DJ et al. Family-based and case–control study of catechol O-methyltransferase in schizophrenia among Palestinian Arabs. Am J Med Genet 2003; 119B: 35–39.

    Article  CAS  Google Scholar 

  25. Wonodi I, Stine OC, Mitchell BD, Buchanan RW, Thanker GK . Association between Val108/158Met polymorphism of the COMT gene and schizophrenia. Am J Med Genet 2003; 120B: 47–50.

    Article  Google Scholar 

  26. Munafò MR, Flint J . Meta-analysis of genetic association studies. Trends Genet 2004; 20: 439–444.

    Article  Google Scholar 

Download references

Acknowledgements

Marcus Munafò is funded by a Cancer Research UK Research Fellowship. Taane Clark is funded by a NHS R&D Research Training Fellowship. Jonathan Flint is supported by the Wellcome Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M R Munafò.

Additional information

References 8–25 indicate studies included in the meta-analyses.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Munafò, M., Bowes, L., Clark, T. et al. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies. Mol Psychiatry 10, 765–770 (2005). https://doi.org/10.1038/sj.mp.4001664

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001664

Keywords

This article is cited by

Search

Quick links