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:

Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families

Molecular Psychiatry volume 9, pages 962–967 (2004)Cite this article

Abstract

The enzyme catechol-o-methyltransferase (COMT) transfers a methyl group from adenosylmethionine to catecholamines including the neurotransmitters dopamine, epinephrine and norepinephrine. This methylation results in the degradation of catecholamines. The involvement of the COMT gene in the metabolic pathway of these neurotransmitters has made it an attractive candidate gene for many psychiatric disorders. In this article, we reported our study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia. Three single nucleotide polymorphisms (SNPs) were genotyped for the 274 such families and within-family transmission disequilibrium tests were performed. SNP rs4680, which is the functional Val/Met polymorphism, showed modest association with the disease by the TRANSMIT, FBAT and PDT programs, while the other two SNPs were negative. These SNPs showed lower level of LDs with each other in the Irish subjects than in Ashkenazi Jews. Haplotype analysis indicated that a haplotype, haplotype A-G-A for SNPs rs737865-rs4680-rs165599, was preferentially transmitted to the affected subjects. This was different from the reported G-G-G haplotype found in Ashkenazi Jews, but both haplotypes shared the Val allele. We concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Hermann MM et al. Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 2003; 116: 127–137.

    Article  CAS  PubMed  Google Scholar 

  2. Gill M, Vallada H, Collier D, Sham P, Holmans P, Murray R et al. A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22). Am J Med Genet 1996; 67: 40–45.

    Article  CAS  PubMed  Google Scholar 

  3. Hovatta I, Lichtermann D, Juvonen H, Suvisaari J, Terwilliger JD, Arajarvi R et al. Linkage analysis of putative schizophrenia gene candidate regions on chromosomes 3p, 5q, 6p, 8p, 20p and 22q in a population-based sampled Finnish family set. Mol Psychiatry 1998; 3: 452–457.

    Article  CAS  PubMed  Google Scholar 

  4. Liu H, Abecasis GR, Heath SC, Knowles A, Demars S, Chen YJ et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002; 99: 16859–16864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68: 661–673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Riley B, Mogudi-Carter M, Jenkins T, Williamson R . No evidence for linkage of chromosome 22 markers to schizophrenia in southern African Bantu-speaking families. Am J Med Genet 1996; 67: 515–522.

    Article  CAS  PubMed  Google Scholar 

  7. Straub RE, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C et al. Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. Mol Psychiatry 2002; 7: 542–559.

    Article  CAS  PubMed  Google Scholar 

  8. Williams NM, Rees MI, Holmans P, Norton N, Cardno AG, Jones LA et al. A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs. Hum Mol Genet 1999; 8: 1729–1739.

    Article  CAS  PubMed  Google Scholar 

  9. Vogels A, Verhoeven WM, Tuinier S, DeVriendt K, Swillen A, Curfs LM et al. The psychopathological phenotype of velo-cardio-facial syndrome. Ann Genet 2002; 45: 89–95.

    Article  CAS  PubMed  Google Scholar 

  10. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 1995; 92: 7612–7616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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  PubMed  Google Scholar 

  13. Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC et al. Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000; 5: 77–84.

    Article  CAS  PubMed  Google Scholar 

  14. 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  PubMed  Google Scholar 

  15. Rybakowski JK, Borkowska A, Czerski PM, Hauser J . Eye movement disturbances in schizophrenia and a polymorphism of catechol-O-methyltransferase gene. Psychiatry Res 2002; 113: 49–57.

    Article  CAS  PubMed  Google Scholar 

  16. 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  PubMed  PubMed Central  Google Scholar 

  17. Strous RD, Bark N, Parsia SS, Volavka J, Lachman HM . Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res 1997; 69: 71–77.

    Article  CAS  PubMed  Google Scholar 

  18. Geller B, Cook Jr EH . Ultradian rapid cycling in prepubertal and early adolescent bipolarity is not in transmission disequilibrium with val/met COMT alleles. Biol Psychiatry 2000; 47: 605–609.

    Article  PubMed  Google Scholar 

  19. Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G et al. Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 1996; 67: 468–472.

    Article  CAS  PubMed  Google Scholar 

  20. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 2003; 100: 6186–6191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rujescu D, Giegling I, Gietl A, Hartmann AM, Moller HJ . A functional single nucleotide polymorphism (V158 M) in the COMT gene is associated with aggressive personality traits. Biol Psychiatry 2003; 54: 34–39.

    Article  CAS  PubMed  Google Scholar 

  22. Tsai SJ, Yu YW, Chen TJ, Chen JY, Liou YJ, Chen MC et al. Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females. Neurosci.Lett 2003; 338: 123–126.

    Article  CAS  PubMed  Google Scholar 

  23. 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  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  25. Fan JB, Chen WY, Tang JX, Li S, Gu NF, Feng GY et al. Family-based association studies of COMT gene polymorphisms and schizophrenia in the Chinese population. Mol Psychiatry 2002; 7: 446–447.

    Article  CAS  PubMed  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T et al. Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 1997; 7: 97–101.

    Article  CAS  PubMed  Google Scholar 

  28. Semwal P, Prasad S, Bhatia T, Deshpande SN, Wood J, Nimgaonkar VL et al. Family-based association studies of monoaminergic gene polymorphisms among North Indians with schizophrenia. Mol Psychiatry 2001; 6: 220–224.

    Article  CAS  PubMed  Google Scholar 

  29. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen 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  PubMed  Google Scholar 

  30. Bray NJ, Buckland PR, Williams NM, Williams HJ, Norton N, Owen MJ et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 2003; 73: 152–161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kendler KS, MacLean CJ, O'Neill FA, Burke J, Murphy B, Duke F et al. Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families. Am J Psychiatry 1996; 153: 1534–1540.

    Article  CAS  PubMed  Google Scholar 

  32. Kendler KS, Myers JM, O'Neill FA, Martin R, Murphy B, MacLean CJ et al. Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of High-Density Schizophrenia Families. Am J Psychiatry 2000; 157: 402–408.

    Article  CAS  PubMed  Google Scholar 

  33. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et al. Genetic variation in the 6p22.3 gene DTNBP1 . the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. American Psychiatric Association. Diagnostic and statistical manual of mental disorders Edition III-R. 3rd edn 1987.

  35. Kendler KS, McGuire M, Gruenberg AM, Spellman M, O′Hare A, Walsh D . The Roscommon Family Study. II. The risk of nonschizophrenic nonaffective psychoses in relatives. Arch Gen Psychiatry 1993; 50: 645–652.

    Article  CAS  PubMed  Google Scholar 

  36. Chen X, Levine L, Kwok PY . Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res 1999; 9: 492–498.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. van den Oord EJ, Jiang Y, Riley BP, Kendler KS, Chen X . FP-TDI SNP scoring by manual and statistical procedures: a study of error rates and types. Biotechniques 2003; 34: 610–620, 622.

    Article  CAS  PubMed  Google Scholar 

  38. Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Clayton D, Jones H . Transmission/disequilibrium tests for extended marker haplotypes. Am J Hum Genet 1999; 65: 1161–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Horvath S, Xu X, Laird NM . The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 2001; 9: 301–306.

    Article  CAS  PubMed  Google Scholar 

  41. Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19(Suppl 1): S36–S42.

    Article  PubMed  Google Scholar 

  42. Martin ER, Monks SA, Warren LL, Kaplan NL . A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 2000; 67: 146–154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sobel E, Lange K . Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 1996; 58: 1323–1337.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 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  PubMed  Google Scholar 

  45. Wei J, Hemmings GP . Lack of evidence for association between the COMT locus and schizophrenia. Psychiatr Genet 1999; 9: 183–186.

    Article  CAS  PubMed  Google Scholar 

  46. Risch N, de Leon D, Ozelius L, Kramer P, Almasy L, Singer B et al. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 1995; 9: 152–159.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Yihua Che and Ms Shoan Hossain for their technical assistance for PCR primer design and optimization. This study is supported by research grant (RO1MH41953) to KSK from the National Institute of Mental Health.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA

    X Chen, X Wang & K S Kendler

  2. The Department of Psychiatry, The Queens University, Belfast, Northern Ireland

    A F O'Neill

  3. The Health Research Board, Dublin, Ireland

    D Walsh

Authors
  1. X Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A F O'Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K S Kendler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, X., Wang, X., O'Neill, A. et al. Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiatry 9, 962–967 (2004). https://doi.org/10.1038/sj.mp.4001519

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001519

Keywords

This article is cited by

Search

Advanced search

Quick links