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:

COMT haplotypes suggest P2 promoter region relevance for schizophrenia

Molecular Psychiatry volume 9, pages 859–870 (2004)Cite this article

Abstract

A recent study found, in a large sample of Ashkenazi Jews, a highly significant association between schizophrenia and a particular haplotype of three polymorphic sites in the catechol-O-methyl transferase, COMT, gene: an IVS 1 SNP (dbSNP rs737865), the exon 4 functional SNP (Val158Met, dbSNP rs165688), and a downstream SNP (dbSNP rs165599). Subsequently, this haplotype was shown to be associated with lower levels of COMT cDNA derived from normal cortical brain tissue, most likely due to cis-acting element(s). As a first step toward evaluating whether this haplotype may be relevant to schizophrenia in populations other than Ashkenazi Jews, we have studied this haplotype in 38 populations representing all major regions of the world. Adding to our previous data on four polymorphic sites in the COMT gene, including the Val158Met polymorphism, we have typed the IVS 1 rs737865 and 3′ rs615599 sites and also included a novel IVS 1 indel polymorphism, yielding seven-site haplotype frequencies for normal individuals in the 38 globally distributed populations, including a sample of Ashkenazi Jews. We report that the schizophrenia-associated haplotype is significantly heterogeneous in populations worldwide. The three-site, schizophrenia-associated haplotype frequencies range from 0% in South America to 37.1% in Southwest Asia, despite the fact that schizophrenia occurs at roughly equal frequency around the world. Assuming that the published associations found between the exon 4 Val158Met SNP and schizophrenia are due to linkage disequilibrium, these new haplotype data support the hypothesis of a relevant cis variant linked to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain. The previously described HindIII restriction site polymorphism, located within the P2 promoter, varies within all populations and may provide essential information in future studies of schizophrenia.

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. 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 

  2. 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 

  3. DeMille MM, Kidd JR, Ruggeri V, Palmatier MA, Goldman D, Odunsi A et al. Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. Hum Genet 2002; 111: 521–537.

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC et al. Errata: Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000; 5: 452.

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Bilder RM, Volavka J, Czobor P, Malhotra AK, Kennedy JL, Ni X et al. Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 2002; 52: 701–707.

    Article  CAS  PubMed  Google Scholar 

  8. Murphy KC, Jones LA, Owen MJ . High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56: 940–945.

    Article  CAS  PubMed  Google Scholar 

  9. Karoum F, Chrapusta SJ, Egan MF . 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem 1994; 63: 972–979.

    Article  CAS  PubMed  Google Scholar 

  10. Sklar P . Linkage analysis in psychiatric disorders: the emerging picture. Annu Rev Genomics Hum Genet 2002; 3: 371–413.

    CAS  PubMed  Google Scholar 

  11. O’Donovan MC, Williams NM, Owen MJ . Recent advances in the genetics of schizophrenia. Hum Mol Genet 2003; 12: R125–R133.

    Article  PubMed  Google Scholar 

  12. Maier W, Zobel A, Rietschel M . Genetics of schizophrenia and affective disorders. Pharmacopsychiatry 2003; 36(Suppl 3): 195–202.

    Google Scholar 

  13. Pulver AE . Search for schizophrenia susceptibility genes. Biol Psychiatry 2000; 47: 221–230.

    Article  CAS  PubMed  Google Scholar 

  14. Riley BP, McGuffin P . Linkage and associated studies of schizophrenia. Am J Med Genet 2000; 97: 23–44.

    Article  CAS  PubMed  Google Scholar 

  15. Williams NM, Norton N, Williams H, Ekholm B, Hamshere ML, Lindblom Y et al. A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 2003; 73: 1355–1367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bertocci B, Miggiano V, Da Prada M, Dembic Z, Lahm HW, Malherbe P . Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. Proc Natl Acad Sci USA 1991; 88: 1416–1420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, Savolainen R, Ulmanen I . Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 1994; 223: 1049–1059.

    Article  CAS  PubMed  Google Scholar 

  18. Lundstrom K, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Ulmanen I . Cloning, expression and structure of catechol-O-methyltransferase. Biochim Biophys Acta 1995; 1251: 1–10.

    Article  CAS  PubMed  Google Scholar 

  19. Palmatier MA, Kang AM, Kidd KK . Global variation in the frequencies of functionally different catechol-O-methyl transferase alleles. Biol Psychiatry 1999; 46: 557–567.

    Article  CAS  PubMed  Google Scholar 

  20. Matsumoto M, Weickert CS, Beltaifa S, Kolachana B, Chen J, Hyde TM et al. Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia. Neuropsychopharmacology 2003; 28: 1521–1530.

    Article  CAS  PubMed  Google Scholar 

  21. Tunbridge E, Burnet PWJ, Sodhi S, Harrision PJ . Catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression. Synapse 2004; 51: 112–118.

    Article  CAS  PubMed  Google Scholar 

  22. Iyengar S, Seaman M, Deinard AS, Rosenbaum HC, Sirugo G, Castiglione CM et al. Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms. DNA Seq 1998; 8: 317–327.

    Article  CAS  PubMed  Google Scholar 

  23. Hawley ME, Kidd KK . HAPLO: a program using the EM algorithm to estimate the frequencies of multi-site haplotypes. J Hered 1995; 86: 409–411.

    Article  CAS  PubMed  Google Scholar 

  24. Lewontin R . The interaction of selection and linkage. I. General considerations: heterotic models. Genetics 1964; 49: 49–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao H, Pakstis AJ, Kidd JR, Kidd KK . Assessing linkage disequilibrium in a complex genetic system. I. Overall deviation from random association. Ann Hum Genet 1999; 63: 167–179.

    Article  CAS  PubMed  Google Scholar 

  26. Devlin B, Risch N . A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 1995; 29: 311–322.

    Article  CAS  PubMed  Google Scholar 

  27. Pakstis AJ, Kidd JR, Kidd KK . A reference distribution of Fst values for biallelic DNA markers. Am J Hum Genet 2002; 71(Suppl): 371.

    Google Scholar 

  28. Calafell F, Grigorenko EL, Chikanian AA, Kidd KK . Haplotype evolution and linkage disequilibrium: a simulation study. Hum Hered 2001; 51: 85–96.

    Article  CAS  PubMed  Google Scholar 

  29. Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman 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 

  30. 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 

  31. 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 

  32. Strous RD, Nolan KA, Lapidus R, Diaz L, Saito T, Lachman HM . Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. Am J Med Genet 2003; 120B: 29–34.

    Article  PubMed  Google Scholar 

  33. 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  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Valeria Ruggeri, Roy Capper, and Lena Golovyan for their technical help. This work was supported by PHS grants, MH62495, AA09379 and GM57672, to KKK and NS01795 to MAP. We want to acknowledge and thank the following additional individuals for their help over the years in assembling the samples from the diverse populations: FL Black, William Byerley, LL Cavalli-Sforza, J Friedlaender, Kenneth Kendler, William Knowler, Frank Oronsaye, Leena Peltonen, Leslie O Schulz and Kenneth Weiss. Some cell lines were made available by the Coriell Institute for Medical Research and by the National Laboratory for the Genetics of Israeli Populations. Special thanks are due to the many hundreds of individuals who volunteered to give blood samples for studies such as this. Without such participation of individuals from diverse parts of the world, we would be unable to obtain a true picture of the genetic variation in our species.

Author information

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    M A Palmatier, A J Pakstis, W Speed, P Paschou, J R Kidd, M M C DeMille & K K Kidd

  2. Neurogenetics Laboratory, NIAAA, Rockville, MD, USA

    D Goldman

  3. Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA

    A Odunsi

  4. Department of Obstetrics and Gynecology, Faculty of Medicine, University of Benin, Benin City, Nigeria

    F Okonofua

  5. The Hubert Kairuki Memorial University, Dar es Salaam, Tanzania

    S Kajuna & N Karoma

  6. Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania

    S Kungulilo

  7. Child Study Center and Department of Psychology, Yale University, New Haven, CT, USA

    E Grigorenko

  8. NI Vavilov Institute of General Genetics RAS, Moscow, Russia

    O V Zhukova

  9. Department of Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    B Bonne-Tamir

  10. Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, ROC, Taiwan

    R-B Lu

  11. Psychiatry Department, Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark

    J Parnas

Authors
  1. M A Palmatier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A J Pakstis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Speed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Paschou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Goldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Odunsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F Okonofua
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Kajuna
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. N Karoma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Kungulilo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E Grigorenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. O V Zhukova
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. B Bonne-Tamir
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R-B Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Parnas
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J R Kidd
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M M C DeMille
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. K K Kidd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K K Kidd.

Additional information

Electronic-Database Information

ALFRED is a database of allele frequency information accessible over the worldwide web at the URL; http://alfred.med.yale.edu/

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palmatier, M., Pakstis, A., Speed, W. et al. COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Mol Psychiatry 9, 859–870 (2004). https://doi.org/10.1038/sj.mp.4001496

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001496

Keywords

This article is cited by

Search

Advanced search

Quick links