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 Article
  • Published:

The complex global pattern of genetic variation and linkage disequilibrium at catechol-O-methyltransferase

Abstract

Genetic variation at the catechol-O-methyltransferase (COMT) gene has been significantly associated with risk for various neuropsychiatric conditions such as schizophrenia, panic disorder, bipolar disorders, anorexia nervosa and others. It has also been associated with nicotine dependence, sensitivity to pain and cognitive dysfunctions especially in schizophrenia. The non-synonymous single nucleotide polymorphism (SNP) in exon 4—Val108/158Met—is the most studied SNP at COMT and is the basis for most associations. It is not, however, the only variation in the gene; several haplotypes exist across the gene. Some studies indicate that the haplotypic combinations of alleles at the Val108/158Met SNP with those in the promoter region and in the 3′-untranslated region are responsible for the associations with disorders and not the non-synonymous SNP by itself. We have now studied DNA samples from 45 populations for 63 SNPs in a region of 172 kb across the region of 22q11.2 encompassing the COMT gene. We focused on 28 SNPs spanning the COMT-coding region and immediately flanking DNA, and found that the haplotypes are from diverse evolutionary lineages that could harbor as yet undetected variants with functional consequences. Future association studies should be based on SNPs that define the common haplotypes in the population(s) being studied.

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

Access options

Buy this article

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. 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. Erratum in: Mol Psychiatry 2000; 5: 452.

    Article  CAS  Google Scholar 

  2. 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; 9: 6917–6922.

    Article  Google Scholar 

  3. 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 

  4. Shifman S, Bronstein M, Sternfeld M, Pisanté A, Weizman A, Reznik I et al. COMT: a common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2004; 128: 61–64.

    Article  Google Scholar 

  5. Pooley EC, Fineberg N, Harrison PJ . The met(158) allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case–control study and meta-analysis. Mol Psychiatry 2007; 12: 556–561.

    Article  CAS  Google Scholar 

  6. Tunbridge EM, Weinberger DR, Harrison PJ . A novel protein isoform of catechol O-methyltransferase (COMT): brain expression analysis in schizophrenia and bipolar disorder and effect of Val158Met genotype. Mol Psychiatry 2006; 11: 116–117.

    Article  CAS  Google Scholar 

  7. Tunbridge EM, Lane TA, Harrison PJ . Expression of multiple catechol-o-methyltransferase (COMT) mRNA variants in human brain. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 834–839.

    Article  Google Scholar 

  8. Tenhunen J, Salminen M, Lundström 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  Google Scholar 

  9. Weinshilboum RM, Raymond FA . Inheritance of low erythrocyte catechol-o-methyltransferase activity in man. Am J Hum Genet 1977; 29: 125–135.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM . 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 

  11. 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 

  12. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004; 75: 807–821. Erratum in: Am J Hum Genet. 2005; 76: 1089.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Lang UE, Bajbouj M, Sander T, Gallinat J . Gender-dependent association of the functional catechol-O-methyltransferase Val158Met genotype with sensation seeking personality trait. Neuropsychopharmacology 2007; 32: 1950–1955.

    Article  CAS  Google Scholar 

  15. Domschke K, Freitag CM, Kuhlenbaumer G, Schirmacher A, Sand P, Nyhuis P et al. Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 2004; 7: 183–188.

    Article  CAS  Google Scholar 

  16. Beuten J, Payne TJ, Ma JZ, Li MD . Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations. Neuropsychopharmacology 2006; 31: 675–684.

    Article  CAS  Google Scholar 

  17. Funke B, Malhotra AK, Finn CT, Plocik AM, Lake SL, Lencz T et al. COMT genetic variation confers risk for psychotic and affective disorders: a case control study. Behav Brain Funct 2005; 1: 19.

    Article  Google Scholar 

  18. Williams HJ, Glaser B, Williams NM, Norton N, Zammit S, Macgregor S et al. No association between schizophrenia and polymorphisms in COMT in two large samples. Am J Psychiatry 2005; 162: 1736–1738.

    Article  Google Scholar 

  19. Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY et al. Catechol-O-methyltransferase gene val/met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 2005; 57: 139–144.

    Article  CAS  Google Scholar 

  20. Palmatier MA, Pakstis AJ, Speed W, Paschou P, Goldman D, Odunsi A et al. COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Mol Psychiatry 2004; 9: 859–870.

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005; 14: 135–143.

    Article  CAS  Google Scholar 

  23. Hu Z, Song CG, Lu JS, Luo JM, Shen ZZ, Huang W et al. A multigenic study on breast cancer risk associated with genetic polymorphisms of ER Alpha, COMT and CYP19 gene in BRCA1/BRCA2 negative Shanghai women with early onset breast cancer or affected relatives. J Cancer Res Clin Oncol 2007; 133: 969–978.

    Article  CAS  Google Scholar 

  24. Kidd JR, Pakstis AJ, Zhao H, Lu RB, Okonofua FE, Odunsi A et al. Haplotypes and linkage disequilibrium at the phenylalanine hydroxylase locus, PAH, in a global representation of populations. Am J Hum Genet 2000; 66: 1882–1899.

    Article  CAS  Google Scholar 

  25. Cubells JF, Kobayashi K, Nagatsu T, Kidd KK, Kidd JR, Calafell F et al. Population genetics of a functional variant of the dopamine beta-hydroxylase gene (DBH). Am J Med Genet 1997; 74: 374–379.

    Article  CAS  Google Scholar 

  26. 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  Google Scholar 

  27. Zhang S, Pakstis AJ, Kidd KK, Zhao H . Comparisons of two methods for haplotype reconstruction and haplotype frequency estimation from population data. Am J Hum Genet 2001; 69: 906–912.

    Article  CAS  Google Scholar 

  28. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  Google Scholar 

  29. Stephens M, Scheet P . Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 2005; 76: 449–462.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 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  Google Scholar 

  33. Gu S, Pakstis AJ, Kidd KK . HAPLOT: a graphical comparison of haplotype blocks, tagSNP sets and SNP variation for multiple populations. Bioinformatics 2005; 21: 3938–3939.

    Article  CAS  Google Scholar 

  34. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 2002; 419: 832–837.

    Article  CAS  Google Scholar 

  35. Patterson N, Richter DJ, Gnerre S, Lander ES, Reich D . Genetic evidence for complex speciation of humans and chimpanzees. Nature 2006; 441: 1103–1108.

    Article  CAS  Google Scholar 

  36. Kidd KK, Pakstis AJ, Speed WC, Kidd JR . Understanding human DNA sequence variation. J Hered 2004; 95: 406–420.

    Article  CAS  Google Scholar 

  37. Sawyer SL, Mukherjee N, Pakstis AJ, Feuk L, Kidd JR, Brookes AJ et al. Linkage disequilibrium patterns vary substantially among populations. Eur J Hum Genet 2005; 13: 677–686.

    Article  CAS  Google Scholar 

  38. Gu S, Pakstis AJ, Li H, Speed WC, Kidd JR, Kidd KK . Significant variation in haplotype block structure but conservation in tagSNP patterns among global populations. Eur J Hum Genet 2007; 15: 302–312. Erratum in: Eur J Hum Genet. 2007; 15: 818.

    Article  CAS  Google Scholar 

  39. Han Y, Gu S, Oota H, Osier MV, Pakstis AJ, Speed WC et al. Evidence of positive selection on a class I ADH locus. Am J Hum Genet 2007; 80: 441–456.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded in part by National Institute of Health grant GM057672 (to JRK) and in part by NIH grant AA009379 (to KKK). We acknowledge Dr Sheng Gu for his help with the various computer programs such as HAPLOT and P-Select. We thank Eva Straka and Daniel Votava for their excellent technical help. We also acknowledge and thank the following people who helped assemble the samples from the diverse populations: FL Black, LL Cavalli-Sforza, K Dumars, J Friedlaender, K Kendler, W Knowler, F Oronsaye, J Parnas, L Peltonen, L O Schulz, D Upson, EL Grigorenko, NJ Karoma, JJ Kim, R-B Lu, A Odunsi, F Okonofua, OV Zhukova and K Weiss. In addition, some of the cell lines were obtained from the National Laboratory for the Genetics of Israeli Populations at Tel Aviv University, and the African American samples were obtained from the Coriell Institute for Medical Research. Special thanks are due to the many hundreds of individuals who volunteered to give blood samples. 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

Authors

Corresponding author

Correspondence to J R Kidd.

Additional information

Websites used:

ALFRED: http://alfred.med.yale.edu/alfred/index.asp

UCSC: genome browser: http://genome.ucsc.edu/

BLAT: http://genome.ucsc.edu/cgi-bin/hgBlat

dbSNP homepage: http://www.ncbi.nlm.nih.gov/SNP/

BLAST: http://www.ncbi.nlm.nih.gov/blast/Blast.cgi.

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mukherjee, N., Kidd, K., Pakstis, A. et al. The complex global pattern of genetic variation and linkage disequilibrium at catechol-O-methyltransferase. Mol Psychiatry 15, 216–225 (2010). https://doi.org/10.1038/mp.2008.64

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.64

Keywords

This article is cited by

Search

Quick links