Skip to main content
SpringerLink
Log in

Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Catechol-O-methyltransferase (COMT) inactivates circulating catechol hormones, catechol neurotransmitters, and xenobiotic catecholamines by methylating their catechol moieties. The COMT gene has been suggested as a candidate gene for schizophrenia through linkage analyses and molecular studies of velo-cardio-facial syndrome. A coding polymorphism of the COMT gene at codon 108/158 (soluble/membrane-bound form) causing a valine to methionine substitution has been shown to influence enzyme activity, but its association with schizophrenia is inconclusive. We have screened 17 known polymorphisms of the COMT gene in 320 Korean schizophrenic patients and 379 controls to determine whether there is a positive association with a nonsynonymous single-nucleotide polymorphism (rs6267) at codon 22/72 (soluble/membrane-bound form) causing an alanine-to-serine (Ala/Ser) substitution. With the Ala/Ala genotype as a reference group, the combined genotype (Ala/Ser and Ser/Ser)-specific adjusted odds ratio was 1.82 (95% CI=1.19–2.76; P=0.005), suggesting the Ser allele as a risk allele for schizophrenia. However, the Val/Met polymorphism was not associated with an increased risk of schizophrenia in Koreans (OR=0.88, 95% CI=0.64–1.21; P=0.43). The Ala72Ser substitution was correlated with reduced COMT enzyme activity. Our results support previous reports that the COMT haplotype implicated in schizophrenia is associated with low COMT expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, DSM-IV, 4th ed. American Psychiatric Association, Washington DC

    Google Scholar 

  • Axelrod J, Tomchick R (1958) Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 233:702–705

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Boudikova B, Szumlanski C, Maidak B, Weinshilboum R (1990) Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Ther 48:381–389

    Article  Google Scholar 

  • Bray NJ, Buckland PR, Williams NM, Williams HJ, Norton N, Owen MJ, O’Donovan MC (2003) A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 73:152–161

    Article  CAS  PubMed  Google Scholar 

  • Bromet E, Fennig S (1999) Epidemiology and natural history of schizophrenia. Biol Psychiatry 46:871–881

    Article  Google Scholar 

  • Brzustowicz L, Honer W, Chow E, Little D, Hogan J, Hodgkinson K, Bassett AS (1999) Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genet 65:1096–1103

    Article  Google Scholar 

  • Brzustowicz L, Hodgkinson K, Chow E, Honer W, Bassett A (2000) Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 288:678–682

    Article  Google Scholar 

  • Carlsson A (1988) The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1:179–186

    CAS  PubMed  Google Scholar 

  • Chen CH, Lee YR, Wei FC, Koong FJ, Hwu HG, Hsiao KJ (1997) Association study of NlaIII and MspI genetic polymorphisms of erythrocyte catechol-O-methyltransferase gene and susceptibility to schizophrenia. Biol Psychiatry 41:985–987

    Article  Google Scholar 

  • Chen CH, Lee YR, Chung MY, Wei FC, Koong FJ, Shaw CK, Yeh JI, Hsiao KJ (1999) Systemic mutation analysis of the catechol-O-methyltransferase gene as a candidate gene for schizophrenia. Am J Psychiatry 156:1273–1275

    Google Scholar 

  • Cohn CK, Dunner DL, Axelrod J (1970) Reduced catechol-O-methyltransferase activity in red blood cell of women with primary affective disorder. Science 170:1323–1324

    Google Scholar 

  • Daniels JK, Williams NM, Williams J, Jones LA, Cardno AG, Murphy KC, Spurlock G, Riley B, Scambler P, Asherson P, McGuffin P, Owen MJ (1996) No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity. Am J Psychiatry 153:268–270

    Google Scholar 

  • Dunham I, Collins J, Wadey R, Scambler P (1992) Possible role for COMT in psychosis associated with velo-cardio-facial syndrome. Lancet 340:1361–1362

    Article  Google Scholar 

  • Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98:6917–6922

    Article  CAS  PubMed  Google Scholar 

  • Gershon ES, Jonas WZ (1975) Erythrocyte soluble catechol-O-methyltransferase activity in primary affective disorder. Arch Gen Psychiatry 32:1351–1356

    Google Scholar 

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

    Article  Google Scholar 

  • Grossman MH, Littrell JB, Weinstein R, Szumlanski C, Weinshilboum RM (1992) Identification of the possible molecular basis for inherited differences in human catechol-O-methyltransferase. Trans Neurosci Soc (Abstr) 18:70

    Google Scholar 

  • Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, Eisen H, Childs B, Kazazian HH, Kucherlapati R, Antonarakis SE, Pulver AE, Housman DE (1995) Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 92:7612–7616

    Google Scholar 

  • Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, Gogos JA (1997) Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci USA 94:4572–4575

    Article  CAS  PubMed  Google Scholar 

  • Kremer I, Pinto M, Murad I, Muhaheed M, Bannoura I, Muller DJ, Schulze TG, Reshef A, Blanaru M, Gathas S, Goichman R, Rietschel M, Dobrusin M, Bachner-Melman R, Nemanov L, Belmaker RH, Maier W, Ebstein RP (2003) Family-based and case-control study of catechol-O-methyltransferase in schizophrenia among Palestinian Arabs. Am J Med Genet 119B: 35–39

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Lachman HM, Nolan KA, Mohr P, Saito T, Volavka J (1998) Association between catechol-O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorder. Am J Psychiatry 155:835–837

    Google Scholar 

  • Lee S, Hong S, Yoon Y, Yang I, Song K (2001) Characterization of publicly available SNPs in the Korean population. Hum Mutat 17:281–284

    Article  Google Scholar 

  • Lewander T, Pongracz G von, Backstrom M, Wetterberg L (1981) Dopamine metabolism in red blood cells in schizophrenia. Clin Genet 19:410–413

    Google Scholar 

  • Lewontin RC (1988) On measures of gametic disequilibrium. Genetics 120:849–852

    CAS  PubMed  Google Scholar 

  • Li T, Sham PC, Vallada H, Xie T, Tang X, Murray RM, Liu X, Collier DA (1996) Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatry Genet 6:131–133

    Google Scholar 

  • Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC, Collier DA (2000) Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 5:77–84 (erratum 5:452)

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol-O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:4202–4210

    CAS  PubMed  Google Scholar 

  • Lundstrom K, Salminen M, Jalanko A, Savolainen R, Ulmanen I (1991) Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA Cell Biol 10:181–189

    Google Scholar 

  • McLeod HL, Syvanen AC, Githang’a J, Indalo A, Ismail D, Dewar K, Ulmanen I, Sludden J (1998) Ethnic differences in catechol-O-methyltransferase pharmacogenetics: frequency of the codon 108/158 low activity allele is lower in Kenyan than Caucasian or south-west Asian individuals. Pharmacogenetics 8:195–199

    Google Scholar 

  • Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor M, Semple C, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9:1415–1423

    Article  Google Scholar 

  • Morrow B, Goldberg R, Carlson C, Gupta RD, Sirotkin H, Collins J, Dunham I, O’Donnell H, Scambler P, Shprintzen R, Kucherlapati R (1995) Molecular definition of the 22q11 deletion in velocardio facial syndrome. Am J Hum Genet 56:1391–1403

    Google Scholar 

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

    Article  Google Scholar 

  • Ohmori O, Shinkai T, Kojima H, Terao T, Suzuki T, Mita T, Abe K (1998) Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenics. Neurosci Lett 243:109–112

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Park TW, Yoon KS, Kim JH, Park WY, Hirvonen A, Kang D (2002) Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia. Eur Neuropsychopharmacol 12:299–303

    Article  Google Scholar 

  • Rivera-Calimlim L, Reilly DK (1984) Difference in erythrocyte catechol-O-methyltransferase activity between Orientals and Caucasians: difference in levodopa tolerance. Clin Pharmacol Ther 35:804–809

    Google Scholar 

  • Saito S, Iida A, Sekine A, Miura Y, Sakamoto T, Ogawa C, Kawauchi S, Higuchi S, Nakamura Y (2001) Identification of 197 genetic variations in six human methyltransferase genes in the Japanese population. J Hum Genet 46:529–537

    Article  CAS  PubMed  Google Scholar 

  • Schwab SG, Lerer B, Albus M, Maier W, Hallmayer J, Fimmers R, Lichtermann D, Minges J, Bondy B, Ackenheil M, Altmark D, Hasib D, Gur E, Ebstein RP, Wildenauer DB (1995) Potential linkage for schizophrenia on chromosome 22q12-q13: a replication study. Am J Med Genet 60:436–443

    Google Scholar 

  • Shield AJ, Thomae BA, Eckloff BW, Wieben ED, Weinshilboum RM (2004) Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 9:151–160

    Article  Google Scholar 

  • Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, Reznik I, Spivak B, Grisaru N, Karp L, Schiffer R, Kotler M, Strous RD, Swartz-Vanetik M, Knobler HY, Shinar E, Beckmann JS, Yakir B, Risch N, Zak NB, Darvasi A (2002) A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71:1296–1302

    Article  CAS  PubMed  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892

    Article  Google Scholar 

  • Straub RE, MacLean CJ, O’Neill FA, Burke J, Murphy B, Duke F, Shinkwin R, Webb BT, Zhang J, Walsh D, Kendler KS (1995) A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity. Nat Genet 11:287–293

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Syvanen AC, Tilgmann C, Rinne J, Ulmanen I (1997) Genetic polymorphism of catechol-O-methyltransferase (COMT): correlation of genotype with individual variation of S-COMT activity and comparison of the allele frequencies in the normal population and Parkinsonian patients in Finland. Pharmacogenetics 7:65–71

    Google Scholar 

  • Tsuang M (2000) Schizophrenia: genes and environment. Biol Psychiatry 47:210–220

    Article  Google Scholar 

  • Weinshilboum RM, Raymond FA (1977) Inheritance of low erythrocyte catechol-O-methyltransferase activity in man. Am J Hum Genet 29:125–135

    Google Scholar 

  • Weinshilboum RM, Raymond FA, Elveback LR, Weidman WH (1974) Correlation of erythrocyte catechol-O-methyltransferase activity between siblings. Nature 252:490–491

    Google Scholar 

  • Xie T, Ho SL, Ramsden D (1999) Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 56:31–38

    Google Scholar 

Download references

Acknowledgements

We thank Yongsook Yoon, Jeongsun Lee, and Sunyoung Lee for excellent technical assistance. This work was supported by the grants to K.S. from the Korean HapMap Project of MOST (Ministry of Science and Technology of Korea) and the Basic Research Grant R04-2004-000-10228-0 of KOSEF.

Author information

Author notes

  1. Seong-Gene Lee

    Present address: Department of Biotechnology, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, Korea

Authors and Affiliations

  1. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Poongnap-Dong, Songpa-Gu, Seoul, 138-736, Korea

    Seong-Gene Lee

  2. Department of Psychiatry, University of Ulsan College of Medicine, Poongnap-Dong, Songpa-Gu, Seoul, 138-736, Korea

    Yeonho Joo, Byungsu Kim, Seockhoon Chung & Changyoon Kim

  3. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 388-1 Poongnap-Dong, Songpa-Gu, Seoul, 138-736, Korea

    Hie-Lim Kim & Kyuyoung Song

  4. Department of Pathology, University of Ulsan College of Medicine, Poongnap-Dong, Songpa-Gu, Seoul, 138-736, Korea

    Inchul Lee

  5. Department of Preventive Medicine, College of Medicine, Hanyang University, Seoul, 133-791, Korea

    Boyoul Choi

Authors
  1. Seong-Gene Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yeonho Joo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Byungsu Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seockhoon Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hie-Lim Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Inchul Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Boyoul Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Changyoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kyuyoung Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyuyoung Song.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, SG., Joo, Y., Kim, B. et al. Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Hum Genet 116, 319–328 (2005). https://doi.org/10.1007/s00439-004-1239-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-004-1239-y

Keywords

Search

Navigation