RBCC

Full text data of COMT

COMT [Confidence: low (only semi-automatic identification from reviews)]
Catechol O-methyltransferase; 2.1.1.6

UniProt P21964
ID COMT_HUMAN Reviewed; 271 AA.
AC P21964; A8MPV9; Q6IB07; Q6ICE6;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1992, sequence version 2.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Catechol O-methyltransferase;
DE EC=2.1.1.6;
GN Name=COMT;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=1707278; DOI=10.1089/dna.1991.10.181;
RA Lundstroem K., Salminen M., Jalanko A., Savolainen R., Ulmanen I.;
RT "Cloning and characterization of human placental catechol-O-
RT methyltransferase cDNA.";
RL DNA Cell Biol. 10:181-189(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-34.
RX PubMed=1847521; DOI=10.1073/pnas.88.4.1416;
RA Bertocci B., Miggiano V., da Prada M., Dembic Z., Lahm H.-W.,
RA Malherbe P.;
RT "Human catechol-O-methyltransferase: cloning and expression of the
RT membrane-associated form.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:1416-1420(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8055944; DOI=10.1111/j.1432-1033.1994.tb19083.x;
RA Tenhunen J., Salminen M., Lundstroem K., Kiviluoto T., Savolainen R.,
RA Ulmanen I.;
RT "Genomic organization of the human catechol O-methyltransferase gene
RT and its expression from two distinct promoters.";
RL Eur. J. Biochem. 223:1049-1059(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-158.
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-72 AND MET-158.
RG NIEHS SNPs program;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT MET-158.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 52-61, AND MASS SPECTROMETRY.
RX PubMed=8020475; DOI=10.1111/j.1432-1033.1994.tb18876.x;
RA Vilbois F., Caspers P., da Prada M., Lang G., Karrer C., Lahm H.W.,
RA Cesura A.M.;
RT "Mass spectrometric analysis of human soluble catechol O-
RT methyltransferase expressed in Escherichia coli. Identification of a
RT product of ribosomal frameshifting and of reactive cysteines involved
RT in S-adenosyl-L-methionine binding.";
RL Eur. J. Biochem. 222:377-386(1994).
RN [12]
RP PROTEIN SEQUENCE OF 59-271.
RC TISSUE=Placenta;
RX PubMed=1993083; DOI=10.1016/0006-291X(91)91517-G;
RA Tilgmann C., Kalkkinen N.;
RT "Purification and partial sequence analysis of the soluble catechol-O-
RT methyltransferase from human placenta: comparison to the rat liver
RT enzyme.";
RL Biochem. Biophys. Res. Commun. 174:995-1002(1991).
RN [13]
RP CHARACTERIZATION OF THE TWO FORMS.
RX PubMed=1765063; DOI=10.1111/j.1432-1033.1991.tb16464.x;
RA Ulmanen I., Lundstroem K.;
RT "Cell-free synthesis of rat and human catechol O-methyltransferase.
RT Insertion of the membrane-bound form into microsomal membranes in
RT vitro.";
RL Eur. J. Biochem. 202:1013-1020(1991).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF 52-264 OF MUTANTS VAL-108 AND
RP MET-108 IN COMPLEX WITH SUBSTRATE ANALOG 3,5-DINITROCATECHOL;
RP MAGNESIUM AND S-ADENOSYL-L-METHIONINE.
RX PubMed=18486144; DOI=10.1016/j.jmb.2008.04.040;
RA Rutherford K., Le Trong I., Stenkamp R.E., Parson W.W.;
RT "Crystal structures of human 108V and 108M catechol O-
RT methyltransferase.";
RL J. Mol. Biol. 380:120-130(2008).
RN [16]
RP VARIANT COMT*2 MET-158.
RX PubMed=8807664;
RA Lachman H.M., Papolos D.F., Saito T., Yu Y.-M., Szumlanski C.L.,
RA Weinshilboum R.M.;
RT "Human catechol-O-methyltransferase pharmacogenetics: description of a
RT functional polymorphism and its potential application to
RT neuropsychiatric disorders.";
RL Pharmacogenetics 6:243-250(1996).
RN [17]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ALCOHOLISM.
RX PubMed=10395222; DOI=10.1038/sj.mp.4000509;
RA Tiihonen J., Hallikainen T., Lachman H., Saito T., Volavka J.,
RA Kauhanen J., Salonen J.T., Ryynaenen O.-P., Koulu M., Karvonen M.K.,
RA Pohjalainen T., Syvaelahti E., Hietala J.;
RT "Association between the functional variant of the catechol-O-
RT methyltransferase (COMT) gene and type 1 alcoholism.";
RL Mol. Psychiatry 4:286-289(1999).
RN [18]
RP VARIANTS SER-34 AND SER-72.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [19]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [20]
RP CHARACTERIZATION OF VARIANT SER-72, AND POSSIBLE INVOLVEMENT IN
RP SCHIZOPHRENIA.
RX PubMed=15645182; DOI=10.1007/s00439-004-1239-y;
RA Lee S.-G., Joo Y., Kim B., Chung S., Kim H.-L., Lee I., Choi B.,
RA Kim C., Song K.;
RT "Association of Ala72Ser polymorphism with COMT enzyme activity and
RT the risk of schizophrenia in Koreans.";
RL Hum. Genet. 116:319-328(2005).
RN [21]
RP CHARACTERIZATION OF VARIANT COMT*2 MET-158.
RX PubMed=18474266; DOI=10.1016/j.bbapap.2008.04.006;
RA Rutherford K., Alphandery E., McMillan A., Daggett V., Parson W.W.;
RT "The V108M mutation decreases the structural stability of catechol O-
RT methyltransferase.";
RL Biochim. Biophys. Acta 1784:1098-1105(2008).
RN [22]
RP VARIANT COMT*2 MET-158.
RX PubMed=18442637; DOI=10.1016/j.metabol.2008.01.012;
RA Annerbrink K., Westberg L., Nilsson S., Rosmond R., Holm G.,
RA Eriksson E.;
RT "Catechol O-methyltransferase val158-met polymorphism is associated
RT with abdominal obesity and blood pressure in men.";
RL Metabolism 57:708-711(2008).
CC -!- FUNCTION: Catalyzes the O-methylation, and thereby the
CC inactivation, of catecholamine neurotransmitters and catechol
CC hormones. Also shortens the biological half-lives of certain
CC neuroactive drugs, like L-DOPA, alpha-methyl DOPA and
CC isoproterenol.
CC -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + a catechol = S-
CC adenosyl-L-homocysteine + a guaiacol.
CC -!- COFACTOR: Binds 1 magnesium ion per subunit.
CC -!- INTERACTION:
CC Q9H0D6:XRN2; NbExp=1; IntAct=EBI-372265, EBI-372110;
CC -!- SUBCELLULAR LOCATION: Isoform Soluble: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform Membrane-bound: Cell membrane;
CC Single-pass type II membrane protein; Extracellular side.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=Membrane-bound; Synonyms=MB-COMT;
CC IsoId=P21964-1; Sequence=Displayed;
CC Name=Soluble; Synonyms=S-COMT;
CC IsoId=P21964-2; Sequence=VSP_018778;
CC -!- TISSUE SPECIFICITY: Brain, liver, placenta, lymphocytes and
CC erythrocytes.
CC -!- PTM: The N-terminus is blocked.
CC -!- MASS SPECTROMETRY: Mass=24352; Mass_error=2; Method=Electrospray;
CC Range=52-271; Source=PubMed:8020475;
CC -!- POLYMORPHISM: Two alleles, COMT*1 or COMT*H with Val-158 and
CC COMT*2 or COMT*L with Met-158 are responsible for a three to four-
CC fold difference in enzymatic activity.
CC -!- POLYMORPHISM: Low enzyme activity alleles are associated with
CC genetic susceptibility to alcoholism [MIM:103780].
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding
CC methyltransferase superfamily. Cation-dependent O-
CC methyltransferase family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/comt/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Catechol-O-methyl transferase
CC entry;
CC URL="http://en.wikipedia.org/wiki/Catechol-O-methyl_transferase";
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DR EMBL; M65212; AAA68927.1; -; mRNA.
DR EMBL; M65213; AAA68928.1; -; mRNA.
DR EMBL; M58525; AAA68929.1; -; mRNA.
DR EMBL; Z26491; CAA81263.1; -; Genomic_DNA.
DR EMBL; AK290440; BAF83129.1; -; mRNA.
DR EMBL; CR456422; CAG30308.1; -; mRNA.
DR EMBL; CR456997; CAG33278.1; -; mRNA.
DR EMBL; AY341246; AAP88929.1; -; Genomic_DNA.
DR EMBL; AC000080; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC000090; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005663; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471176; EAX03010.1; -; Genomic_DNA.
DR EMBL; BC011935; AAH11935.1; -; mRNA.
DR EMBL; BC100018; AAI00019.1; -; mRNA.
DR PIR; I37256; A38459.
DR RefSeq; NP_000745.1; NM_000754.3.
DR RefSeq; NP_001128633.1; NM_001135161.1.
DR RefSeq; NP_001128634.1; NM_001135162.1.
DR RefSeq; NP_009294.1; NM_007310.2.
DR RefSeq; XP_005261286.1; XM_005261229.1.
DR UniGene; Hs.370408; -.
DR UniGene; Hs.713616; -.
DR PDB; 3A7E; X-ray; 2.80 A; A=51-264.
DR PDB; 3BWM; X-ray; 1.98 A; A=52-265.
DR PDB; 3BWY; X-ray; 1.30 A; A=52-265.
DR PDBsum; 3A7E; -.
DR PDBsum; 3BWM; -.
DR PDBsum; 3BWY; -.
DR ProteinModelPortal; P21964; -.
DR SMR; P21964; 52-265.
DR IntAct; P21964; 6.
DR MINT; MINT-4529967; -.
DR STRING; 9606.ENSP00000354511; -.
DR BindingDB; P21964; -.
DR ChEMBL; CHEMBL2023; -.
DR DrugBank; DB00190; Carbidopa.
DR DrugBank; DB00286; Conjugated Estrogens.
DR DrugBank; DB00255; Diethylstilbestrol.
DR DrugBank; DB00841; Dobutamine.
DR DrugBank; DB00988; Dopamine.
DR DrugBank; DB00494; Entacapone.
DR DrugBank; DB00158; Folic Acid.
DR DrugBank; DB00161; L-Valine.
DR DrugBank; DB01235; Levodopa.
DR DrugBank; DB00968; Methyldopa.
DR DrugBank; DB00745; Modafinil.
DR DrugBank; DB00295; Morphine.
DR DrugBank; DB00118; S-Adenosylmethionine.
DR DrugBank; DB00323; Tolcapone.
DR GuidetoPHARMACOLOGY; 2472; -.
DR PhosphoSite; P21964; -.
DR DMDM; 116907; -.
DR REPRODUCTION-2DPAGE; IPI00375513; -.
DR PaxDb; P21964; -.
DR PRIDE; P21964; -.
DR DNASU; 1312; -.
DR Ensembl; ENST00000361682; ENSP00000354511; ENSG00000093010.
DR Ensembl; ENST00000403710; ENSP00000385917; ENSG00000093010.
DR Ensembl; ENST00000406520; ENSP00000385150; ENSG00000093010.
DR Ensembl; ENST00000407537; ENSP00000384654; ENSG00000093010.
DR Ensembl; ENST00000449653; ENSP00000416778; ENSG00000093010.
DR GeneID; 1312; -.
DR KEGG; hsa:1312; -.
DR UCSC; uc002zqu.3; human.
DR CTD; 1312; -.
DR GeneCards; GC22P019929; -.
DR HGNC; HGNC:2228; COMT.
DR HPA; CAB011233; -.
DR HPA; HPA001169; -.
DR MIM; 103780; phenotype.
DR MIM; 116790; gene+phenotype.
DR neXtProt; NX_P21964; -.
DR Orphanet; 567; 22q11.2 deletion syndrome.
DR Orphanet; 240863; Cisplatin toxicity.
DR Orphanet; 240999; Susceptibility to deafness due to cisplatin treatment.
DR PharmGKB; PA117; -.
DR eggNOG; COG4122; -.
DR HOGENOM; HOG000046392; -.
DR HOVERGEN; HBG005376; -.
DR InParanoid; P21964; -.
DR KO; K00545; -.
DR OMA; YSSYLEY; -.
DR OrthoDB; EOG7PZRZJ; -.
DR PhylomeDB; P21964; -.
DR BioCyc; MetaCyc:HS01791-MONOMER; -.
DR BRENDA; 2.1.1.6; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_13685; Neuronal System.
DR ChiTaRS; COMT; human.
DR EvolutionaryTrace; P21964; -.
DR GeneWiki; Catechol-O-methyl_transferase; -.
DR GenomeRNAi; 1312; -.
DR NextBio; 5365; -.
DR PRO; PR:P21964; -.
DR ArrayExpress; P21964; -.
DR Bgee; P21964; -.
DR CleanEx; HS_COMT; -.
DR Genevestigator; P21964; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0016206; F:catechol O-methyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0008171; F:O-methyltransferase activity; TAS:ProtInc.
DR GO; GO:0042420; P:dopamine catabolic process; IEA:Ensembl.
DR GO; GO:0008210; P:estrogen metabolic process; IEA:Ensembl.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0007612; P:learning; IEA:Ensembl.
DR GO; GO:0048609; P:multicellular organismal reproductive process; IEA:Ensembl.
DR GO; GO:0045963; P:negative regulation of dopamine metabolic process; IEA:Ensembl.
DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0042136; P:neurotransmitter biosynthetic process; TAS:Reactome.
DR GO; GO:0042135; P:neurotransmitter catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0050668; P:positive regulation of homocysteine metabolic process; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0048265; P:response to pain; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR InterPro; IPR025782; Catechol_O-MeTrfase.
DR InterPro; IPR017128; Catechol_O-MeTrfase_euk.
DR InterPro; IPR002935; O-MeTrfase_3.
DR PANTHER; PTHR10509; PTHR10509; 1.
DR Pfam; PF01596; Methyltransf_3; 1.
DR PIRSF; PIRSF037177; Catechol_O-mtfrase_euk; 1.
DR PROSITE; PS51682; SAM_OMT_I; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative initiation; Catecholamine metabolism;
KW Cell membrane; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Magnesium; Membrane; Metal-binding;
KW Methyltransferase; Neurotransmitter degradation; Polymorphism;
KW Reference proteome; S-adenosyl-L-methionine; Signal-anchor;
KW Transferase; Transmembrane; Transmembrane helix.
FT CHAIN 1 271 Catechol O-methyltransferase.
FT /FTId=PRO_0000020971.
FT TRANSMEM 7 26 Helical; Signal-anchor for type II
FT membrane protein; (Potential).
FT REGION 167 170 S-adenosyl-L-methionine binding.
FT METAL 191 191 Magnesium.
FT METAL 219 219 Magnesium.
FT METAL 220 220 Magnesium.
FT BINDING 92 92 S-adenosyl-L-methionine; via amide
FT nitrogen.
FT BINDING 114 114 S-adenosyl-L-methionine (By similarity).
FT BINDING 122 122 S-adenosyl-L-methionine.
FT BINDING 140 140 S-adenosyl-L-methionine.
FT BINDING 141 141 S-adenosyl-L-methionine; via amide
FT nitrogen (By similarity).
FT BINDING 169 169 S-adenosyl-L-methionine; via amide
FT nitrogen (By similarity).
FT BINDING 191 191 S-adenosyl-L-methionine.
FT BINDING 194 194 Substrate.
FT BINDING 220 220 Substrate.
FT BINDING 249 249 Substrate.
FT VAR_SEQ 1 50 Missing (in isoform Soluble).
FT /FTId=VSP_018778.
FT VARIANT 34 34 C -> S (in dbSNP:rs6270).
FT /FTId=VAR_013925.
FT VARIANT 72 72 A -> S (correlated with reduced enzyme
FT activity; could be a risk allele for
FT schizophrenia; dbSNP:rs6267).
FT /FTId=VAR_013926.
FT VARIANT 102 102 A -> T (in dbSNP:rs5031015).
FT /FTId=VAR_020274.
FT VARIANT 146 146 A -> V (in dbSNP:rs4986871).
FT /FTId=VAR_020275.
FT VARIANT 158 158 V -> M (in allele COMT*2; associated with
FT low enzyme activity and thermolability;
FT may increase the tendency to develop high
FT blood pressure and abdominal obesity;
FT dbSNP:rs4680).
FT /FTId=VAR_005139.
FT CONFLICT 245 245 Q -> N (in Ref. 12; AA sequence).
FT HELIX 55 66
FT HELIX 72 85
FT HELIX 93 107
FT STRAND 110 115
FT HELIX 121 127
FT STRAND 135 141
FT HELIX 143 155
FT HELIX 159 161
FT STRAND 162 167
FT HELIX 169 172
FT HELIX 173 175
FT HELIX 176 180
FT STRAND 185 190
FT HELIX 194 196
FT HELIX 197 206
FT STRAND 210 219
FT HELIX 221 225
FT HELIX 227 235
FT STRAND 239 247
FT STRAND 251 262
SQ SEQUENCE 271 AA; 30037 MW; D2547A1C399AC758 CRC64;
MPEAPPLLLA AVLLGLVLLV VLLLLLRHWG WGLCLIGWNE FILQPIHNLL MGDTKEQRIL
NHVLQHAEPG NAQSVLEAID TYCEQKEWAM NVGDKKGKIV DAVIQEHQPS VLLELGAYCG
YSAVRMARLL SPGARLITIE INPDCAAITQ RMVDFAGVKD KVTLVVGASQ DIIPQLKKKY
DVDTLDMVFL DHWKDRYLPD TLLLEECGLL RKGTVLLADN VICPGAPDFL AHVRGSSCFE
CTHYQSFLEY REVVDGLEKA IYKGPGSEAG P
//

MIM 103780
*RECORD*
*FIELD* NO
103780
*FIELD* TI
#103780 ALCOHOL DEPENDENCE
;;ALCOHOLISM
*FIELD* TX
A number sign (#) is used with this entry because of the demonstrated
read morerole of multiple genes in determining the genetic susceptibility for
alcoholism that is supported by family, twin, and other studies. See
MOLECULAR GENETICS below.

INHERITANCE

The tendency for drinking patterns of children to resemble those of
their parents has been recognized since antiquity, e.g., in the
observations of Plato and Aristotle (Warner and Rosett, 1975).
Alcoholism is probably a multifactorial, genetically influenced disorder
(Goodwin, 1976). The genetic influence is indicated by studies showing
that (1) there is a 25 to 50% lifetime risk for alcoholism in sons and
brothers of severely alcoholic men; (2) alcohol preference can be
selectively bred for in experimental animals; (3) there is a 55% or
higher concordance rate in monozygotic twins with only a 28% rate for
like-sex dizygotic twins; and (4) half brothers with different fathers
and adopted sons of alcoholic men show a rate of alcoholism more like
that of the biologic father than that of the foster father. A possible
biochemical basis is a metabolic difference such that those prone to
alcoholism have higher levels of a metabolite giving pleasurable effects
or those not prone to alcoholism have higher levels of a metabolite
giving unpleasant effects. Schuckit and Rayses (1979) found that, after
a moderate dose of alcohol, blood acetaldehyde levels were elevated more
in young men with alcoholic parents or sibs than in controls. A certain
degree of organ specificity in the pathologic effects of alcohol is
observed. For example, patients have cardiomyopathy, cirrhosis, or
pancreatitis but rarely more than one of these. A genetic basis of organ
specificity is evident in Wernicke-Korsakoff syndrome (277730) and
pancreatitis from type V hyperlipidemia (144650).

Cloninger (1987) identified 2 separate heritable types of alcoholism.
Type 1 alcohol abuse had its usual onset after the age of 25 years and
was characterized by severe psychological dependence and guilt. It
occurred in both men and women and required both genetic and
environmental factors to become manifest. By contrast, type 2 alcohol
abuse had its onset before the age of 25; persons with this type of
alcoholism were characterized by their inability to abstain from alcohol
and by frequent aggressive and antisocial behavior. Type 2 alcoholism
was rarely found in women and was much more heritable. Abnormalities in
platelet monoamine oxidase activity were found only in type 2 alcoholics
(Von Knorring et al., 1985). See comments by Omenn (1988).

Crabb (1990) reviewed biologic markers for increased risk of alcoholism.
Aston and Hill (1990) performed complex segregation analysis of 35
multigenerational families ascertained through a pair of male
alcoholics. They concluded that liability to alcoholism is, in part,
controlled by a major effect with or without additional multifactorial
effects. However, mendelian transmission of this major effect was
rejected, as was the hypothesis that the major effect is due to a single
major locus.

In connection with a collection of 11 research reports on the genetics
of alcohol-related traits, Buck (1998) gave a brief review on recent
progress toward the identification of genes related to risk for
alcoholism.

MAPPING

Nurnberger et al. (2001) reported linkage data indicating that a
susceptibility locus for alcoholism and/or depression phenotypes resides
on chromosome 1p. Using short tandem repeat (STR) markers and the
transmission disequilibrium test in 87 European-American families with
one or more alcohol-dependent offspring (93 children and 174 parents),
Lappalainen et al. (2004) fine-mapped the region identified by
Nurnberger et al. (2001). The strongest evidence for transmission
disequilibrium was for marker D1S406 (p = 0.005). Three other markers,
all within less than 350 kb, had supporting evidence for transmission
disequilibrium: D1S424 (p = 0.01), D1S2804 (p = 0.04), and D1S2776 (p =
0.02). Lappalainen et al. (2004) suggested that one or more genes
causing susceptibility to alcohol dependence reside on chromosome 1 in a
region approximately delimited by markers D1S1170 and D1S2779.

Event-related brain potentials (ERPs) are recordings of neuroelectric
activity, usually in response to some task, made from electrodes on the
scalp. ERPs are altered in patients with a variety of psychiatric
disorders and in members of their families, compared with the general
population. Alcoholic subjects have a reduction of amplitude of the P3
component, a positive peak approximately 300-600 ms after a stimulus,
that remains after long periods of abstinence from alcohol (Porjesz and
Begleiter, 1985). A similar reduction in P3 amplitude is also seen in
young alcohol-naive sons of alcoholic probands (Begleiter et al., 1984).
Almasy et al. (2001) presented results of a genomewide linkage screen
for amplitude of the N4 and P3 components of the ERP, measured at 19
scalp locations in response to a semantic priming task for 604
individuals in 100 pedigrees ascertained as part of a collaborative
study on the genetics of alcoholism. N4 and P3 amplitudes in response to
3 semantic stimuli showed significant heritabilities, the highest being
0.54. Both N4 and P3 amplitudes showed significant genetic correlations
across stimulus type at a given lead and across leads within a stimulus,
indicating shared genetic influences among the traits. N4 amplitudes
showed suggestive evidence of linkage in several chromosomal regions,
and P3 amplitudes showed significant evidence of linkage to chromosome 5
and suggestive evidence of linkage to chromosome 4.

Ehlers et al. (2004) used a panel of 791 microsatellite polymorphisms to
map susceptibility loci for DSM-III-R alcohol dependence and 2 narrower
alcohol-related phenotypes (alcohol use severity phenotype and
withdrawal phenotype) in Mission Indian families (466 individuals).
Analyses of multipoint variance component lod scores for the dichotomous
DSM-III-R phenotype revealed no peak lod scores that exceeded 2.0. For
the alcohol use severity phenotype, chromosomes 4 and 12 had peak lod
scores that exceeded 2.0, and for the withdrawal phenotype, chromosomes
6, 15, and 16 were found to have peak lod scores that exceeded 2.0.
Combined linkage and association analyses suggested that polymorphisms
of the alcohol dehydrogenase-1B gene (ADH1B; 103720) were partially
responsible for the linkage result on chromosome 4 in this population.

Prescott et al. (2006) conducted a genome scan in the Irish Affected Sib
Pairs Study of Alcohol Dependence sample set. Most of the probands were
ascertained through alcoholism treatment settings and were severely
affected. Probands, affected sibs, and parents were evaluated by
structured interview. Most of the 474 families in the study were
comprised of affected sib pairs (96%). Quantitative results indicated
strong linkage for alcohol dependence criteria (defined by DSM IV) to
chromosome 4q22-4q32 (peak multipoint lod = 4.59, p = 0.0000021 at
D4S1611).

Hill et al. (2004) studied families containing alcoholics (330
individuals) identified through a double proband methodology. Multipoint
linkage analyses using 360 markers for 22 autosomes gave strong support
for loci on chromosomes 1, 2, 6, 7, 10, 12, 14, 16, and 17.

By genomewide ordered subset linkage analysis for alcohol dependence
using admixture proportion as a covariate among African Americans, Han
et al. (2013) found significant linkage to a locus on chromosome 4q
(maximum lod score of 4.2) in a subset of 44 families with an African
ancestry proportion ranging from 0.858 to 0.996. The candidate region
includes the GLRA3 gene (600421), which encodes a subunit of the glycine
neurotransmitter receptor. A second genomewide significant linkage
result was observed on chromosome 22 (lod of 3.23) in a subset of 33
families with a high proportion of African ancestry ranging from 0.885
to 0.996.

CLINICAL MANAGEMENT

George et al. (2008) investigated the role of the neurokinin-1 receptor
(NK1R, or TACR1; 162323), a mediator of behavioral stress responses, in
alcohol dependence and treatment. In preclinical studies, mice
genetically deficient in NK1R showed a marked decrease in voluntary
alcohol consumption and had an increased sensitivity to the sedative
effects of alcohol. In a randomized controlled experimental study,
George et al. (2008) treated recently detoxified alcoholic inpatients
with an NK1R antagonist (n = 25) or placebo (n = 25). The NK1R
antagonist suppressed spontaneous alcohol cravings, improved overall
well-being, blunted cravings induced by a challenge procedure, and
attenuated concomitant cortisol responses. Brain functional magnetic
resonance imaging responses to affective stimuli likewise suggested
beneficial NK1R antagonist effects. George et al. (2008) suggested that
given these surrogate markers of efficacy, NK1R antagonism warrants
further investigation as a treatment in alcoholism.

MOLECULAR GENETICS

Flatscher-Bader et al. (2008) compared gene expression analysis of
postmortem brain tissue from the ventral tegmental area (VTA) of 6
chronic alcoholics and 6 controls. Stringent analysis identified changes
affecting 3 distinct functional themes between the 2 groups: neuron
function, cell signaling, and alcohol and glucose metabolism. Genes
involved in morphologic plasticity were identified in a less stringent
analysis.

- Association with the ADH Gene Cluster on Chromosome 4q22

In a genomewide linkage study in families mostly of European ancestry,
Reich et al. (1998) found evidence that supported the genetic linkage
between alcoholism and the region of chromosome 4 that includes the ADH
genes. In a sample of an Amerindian population, Long et al. (1998) found
evidence that supported the genetic linkage between alcohol dependence
and a nearby region on chromosome 4.

Chai et al. (2005) examined polymorphisms in the ADH2 (ADH1B; 103720)
and ADH3 (ADH1C; 103730) genes on chromosome 4q22 and in the ALDH2
(100650) gene on chromosome 12q24 in 72 alcoholic and 38 nonalcoholic
healthy Korean men. Forty-eight of the alcoholic men had Cloninger type
1 and 24 had Cloninger type 2 alcoholism. The frequency of ADH1B*1 (see
103720.0001) and ADH1C*2 (see 103730.0001) alleles was significantly
higher in men with type 2 alcoholism than in men with type 1 alcoholism
and in healthy men. The frequency of the ALDH2*1 (100650.0001) allele
was significantly higher in men with alcohol dependence than in healthy
men. Chai et al. (2005) suggested that the genetic characteristics of
alcohol metabolism in type 1 alcoholism fall between nonalcoholism and
type 2 alcoholism.

Edenberg et al. (2006) found an association between alcohol dependence
and several SNPs in the ADH4 gene (103740). The SNP showing the greatest
evidence of association (dbSNP rs4148886) yielded a p value of 0.0042;
permutation testing resulted in a global significance of 0.036. The
region of strongest association (p = 0.01) ran from intron 1 to 19.5-kb
beyond the ADH4 gene into the intergenic region between ADH4 and ADH5
(103710).

Using data on in vivo alcohol metabolism obtained from 206 Australian
twin pairs of Caucasian ancestry, Birley et al. (2008) found an
association between SNPs and haplotypes in the ADH7 gene (600086) and
interindividual variation in the early stages of alcohol metabolism. The
patterns of linkage disequilibrium among these SNPs identified a
recombinational hotspot within a 35-kb DNA tract contained in the region
5-prime to intron 7 in the ADH7 gene. The region accounted for 18% of
the linkage for alcohol concentration associated with the ADH region, or
approximately 11% of the genetic variance.

Among 9,080 Caucasian Danish men and women, Tolstrup et al. (2008) found
that those with genotypes encoding slow alcohol metabolism ADH1B*1 (see
103720.0001) and ADH1C*2 (see 103730.0001) drank more alcohol and had
higher risks of alcoholism compared to those with genotypes encoding
faster alcohol metabolism. Effect sizes were smaller for the ADH1C
genotype than for the ADH1B genotype. Since slow ADH1B alcohol
degradation (arg48) is found in more than 90% of the white population
compared to less than 10% of East Asians, the population attributable
risk of heavy drinking and alcoholism by the ADH1B arg48/arg48 genotype
was 67 and 62% among the white population compared with 9 and 24% among
the East Asian population.

In 206 Australian twin pairs, 216 parents, and 226 nontwin sibs, Birley
et al. (2009) genotyped 103 SNPs across the ADH gene cluster region to
test for allelic associations with variation in blood and breath alcohol
concentrations after an alcohol challenge. In vivo alcohol metabolism
was modeled with 3 parameters that identified the absorption and rise of
alcohol concentration following ingestion, and the rate of elimination.
Alleles of ADH7 SNPs were strongly associated (p less than 0.001; dbSNP
rs1154461, dbSNP rs1154468, dbSNP rs1154470, and dbSNP rs894363) with
the early stages of alcohol metabolism, with additional effects seen for
SNPs in the ADH1A, ADH1B, and ADH4 (103740) regions. Rate of elimination
was associated with multiple SNPs in the intragenic region between ADH7
and ADH1C, and across ADH1C and ADH1B. SNPs affecting alcohol metabolism
did not correspond to those reported to affect alcohol dependence or
alcohol-related disease. The combined SNP associations with early- and
late-stage metabolism only accounted for approximately 20% of the total
genetic variance linked to the ADH region, and most of the variance for
in vivo alcohol metabolism linked to this region is yet to be explained.

Macgregor et al. (2009) tested for associations between 9 polymorphisms
in the ALDH2 gene and 41 in the ADH genes, and alcohol-related flushing,
alcohol use, and dependence symptom scores in 4,597 Australian twins,
predominantly of European ancestry. The vast majority (4,296
individuals) had consumed alcohol in the previous year, with 547 meeting
DSM-IIIR criteria for alcohol dependence. There were study-wide
significant associations between dbSNP rs1229984 (103720.0001) and
flushing and consumption, but only nominally significant associations (p
less than 0.01) with alcohol dependence. Individuals carrying the G
allele/arg48 reported a lower prevalence of flushing after alcohol,
consumed alcohol on more occasions, had a higher maximum number of
alcoholic drinks in a single day and a higher overall alcohol
consumption in the previous year than those with the less common A
allele/his48. After controlling for dbSNP rs1229984, an independent
association was observed between dbSNP rs1042026 in the ADH1B gene and
alcohol intake and suggestive associations between alcohol consumption
phenotypes and dbSNP rs1693482 in the ADH1C gene (see 103730.0001),
dbSNP rs1230165 (ADH5; 103710) and dbSNP rs3762894 (ADH4; 103740). ALDH2
variation was not associated with flushing or alcohol consumption, but
was weakly associated with alcohol dependence measures. These results
bridge the gap between DNA sequence variation and alcohol-related
behavior, confirming that the ADH1B R48H polymorphism affects both
alcohol-related flushing in Europeans and alcohol intake.

- Association with the SNCA gene on Chromosome 4q22.1

Bonsch et al. (2005) found an association between the length of the SNCA
REP1 allele and alcohol dependence in 135 Caucasian alcoholic patients
and 101 healthy Caucasian controls. The longer 273- and 271-bp alleles
were more frequent in alcoholic patients compared to controls (p less
than 0.001), and higher SNCA mRNA expression levels were correlated with
the longer SNCA REP1 alleles.

- Association with the DKK2 gene on Chromosome 4q25

Kalsi et al. (2010) conducted a systematic, gene-centric association
study of alcohol dependence using 518 SNPs within the 65 genes of the
linkage peak on chromosome 4q21-q32 identified by Prescott et al.
(2006). Case-only regression analysis with the quantitative variable of
alcohol-dependent symptoms was performed in 562 genetically independent
cases of the Irish Affected Sib Pair Study of Alcohol Dependence
(IASPSAD) sample. Gene-wise correction for multiple testing yielded
empirical evidence of association with 3 SNPs in DKK2 in the cohort
(dbSNP rs427983, dbSNP rs419558, dbSNP rs399087; p less than 0.007). The
association was replicated in 847 cases of European descent from a large
independent sample, the Collaborative Study of the Genetics of
Alcoholism (COGA). Haplotype-specific expression measurements in
postmortem tissue samples suggested a functional role for DKK2.

- Association with the GABA-A Receptor Gene Cluster on Chromosome
5q34

Radel et al. (2005) genotyped a Southwestern Native American sample of
433 individuals and a Finnish sample of 511 individuals, including both
alcohol-dependent and unaffected individuals, for 6 SNPs in the GABA-A
receptor gene cluster (see 137140) on chromosome 5q34. Sib-pair linkage
and case-control association analyses as well as linkage disequilibrium
mapping with haplotypes were done. Radel et al. (2005) detected sib-pair
linkage of 5q34 GABA-A receptor genes to alcohol dependence in both
population samples. Haplotype localization implicated 3 polymorphisms of
GABRA6 (137143), including a pro385-to-ser substitution.

- Association with the NPY Gene on Chromosome 7p15

Kauhanen et al. (2000) and Lappalainen et al. (2002) found an
association between susceptibility to alcoholism and a leu7-to-pro
polymorphism in the neuropeptide Y (NPY) gene on chromosome 7p15; see
162640.0001.

- Association with the TAS2R16 Gene on Chromosome 7q31

Hinrichs et al. (2006) found a functional variant in a bitter-taste
receptor, the TAS2R16 gene (604867) on chromosome 7q31, that influences
risk of alcohol dependence. The lys172 allele of the K172N SNP
(604867.0001) showed an increased risk of alcohol dependence, regardless
of ethnicity. However, this risk allele was uncommon in European
Americans, whereas 45% of African Americans carried the lys172 allele,
which makes this a much more significant risk factor in the African
American population.

- Association with the TAS2R38 Gene on Chromosome 7q35

In a study of 2,309 individuals from 262 families with alcohol
dependence comprising both European American and African American
individuals (the same cohort as studied by Hinrichs et al., 2006), Wang
et al. (2007) found an association between the nontaster haplotype in
the TAS2R38 gene (607751) and maximum alcohol consumption only among
Artican American females. The taster haplotype was associated with lower
maximum alcohol consumption (p = 0.035). However, there was no evidence
that TAS2R38 haplotypes influence alcohol dependence.

- Association with the CHRM2 Gene on Chromosome 7q35

Genomewide linkage analyses using pedigrees from the Collaborative Study
of the Genetics of Alcoholism (COGA) provided consistent evidence of an
alcoholism susceptibility locus on the long arm of chromosome 7 (Reich
et al., 1998; Foroud et al., 2000).

By fine mapping of 488 sib pairs with alcohol dependence, Wang et al.
(2004) refined the locus on chromosome 7q to D7S1799 (lod = 2.9). They
examined 11 SNPs within and flanking the CHRM2 gene (118493) in 262
families with alcohol dependence from the COGA. Three SNPs showed highly
significant association with alcoholism (p = 0.004, 0.004, and 0.007,
respectively). Two SNPs were significantly associated with major
depressive syndrome (MDD; 608516) (p = 0.004 and 0.017). Haplotype
analyses revealed that the most common haplotype, T-T-T (dbSNP
rs1824024, dbSNP rs2061174, and dbSNP rs324650), was undertransmitted to
affected individuals with alcohol dependence and major depressive
syndrome.

Luo et al. (2005) examined the relationships between variation in the
CHRM2 gene and alcohol dependence (AD), drug dependence (DD), and
affective disorders, using a novel extended case-control structured
association method. Six markers at CHRM2 and 38 ancestry-informative
markers were genotyped in a sample of 871 subjects, including 333
healthy controls and 538 AD and/or DD subjects (415 with AD and 346 with
DD). The same CHRM2 markers were genotyped in a sample of 137 subjects
with affective disorders. All 6 markers were in Hardy-Weinberg
equilibrium in controls, but dbSNP rs1824024 was in Hardy-Weinberg
disequilibrium in the AD and DD groups. Regression analysis identified
specific alleles, genotypes, haplotypes, and diplotypes that were
significantly associated with risk for each disorder. Luo et al. (2005)
concluded that variation in the CHRM2 gene may predispose to alcohol
dependence, drug dependence, and affective disorders.

- Association with the ANKK1 Gene (TaqIA Allele) on Chromosome
11q23

In a study of the TaqIA polymorphism (see ANKK1; 608774) in 884
nonalcoholic Finnish Caucasian males, Hallikainen et al. (2003) found
that the self-reported alcohol consumption of the homozygous A1/A1 group
was 30% and 40% lower than that of the A1/A2 and A2/A2 groups,
respectively (p = 0.042).

- Association with the DRD2 Gene on Chromosome 11q23

The candidate gene approach was used by Blum et al. (1990) and by Bolos
et al. (1990) to investigate a possible relationship of the dopamine D2
receptor (DRD2; 126450), which maps to chromosome 11q23, to alcoholism.
Although Blum et al. (1990) suggested an association between a
particular allele at the DRD2 locus, Bolos et al. (1990) could not
confirm this. In family studies, Bolos et al. (1990) excluded linkage
between alcoholism and the DRD2 locus.

Johann et al. (2005) studied the association of a -141C deletion variant
(-141delC) of the DRD2 gene in 1,126 well-characterized, primary chronic
alcoholics of German descent according to a phenotype-genotype strategy
and found an excess of the -141delC alleles in alcoholics with a
paternal and grandpaternal history of alcoholism and in alcoholic
subgroups with suicidality or without a history of withdrawal symptoms.
Johann et al. (2005) concluded that the -141delC variant of DRD2 might
be a protective factor against the development of withdrawal symptoms
but might also be a risk factor in a highly burdened subgroup of
alcoholics with a paternal and grandpaternal history of alcoholism and
might contribute to suicide risk in alcoholics.

- Association with the ALDH2 Gene on Chromosome 12q24

Chai et al. (2005) examined polymorphisms in the ADH2 and ADH3 genes on
chromosome 4q22 and in the ALDH2 (100650) gene on chromosome 12q24 in 72
alcoholic and 38 nonalcoholic healthy Korean men. Forty-eight of the
alcoholic men had Cloninger type 1 and 24 had Cloninger type 2
alcoholism. The frequency of the ALDH2*1 (100650.0001) allele was
significantly higher in men with alcohol dependence than in healthy men.
Also see 'Association with the ADH Gene Cluster on Chromosome 4q22.'

Among 1,032 Korean individuals, Kim et al. (2008) found that the
combination of the ADH1B his48 allele (103720.0001) and the ALDH2 lys504
allele (100650.0001) offered protection against alcoholism. Individuals
who carried both susceptibility alleles (arg48 and glu504, respectively)
had a significantly increased risk for alcoholism (OR, 91.43; p = 1.4 x
10(-32)). Individuals with 1 protective and 1 susceptibility allele had
a lesser increased risk for alcoholism (OR, 11.40; p = 3.5 x 10(-15))
compared to those with both protective alleles. Kim et al. (2008)
calculated that alcoholism in the Korean population is 86.5%
attributable to the detrimental effect of the ADH1B arg48 and/or the
ALDH2 glu504 alleles.

- Association with the NRXN3 Gene on Chromosome 14q

In a genotype study of 144 European Americans with alcohol dependence
and 188 controls, Hishimoto et al. (2007) found an association between
alcohol dependence and the T allele of dbSNP rs8019381, located 23 bp
from the NRXN3 (600567) exon 23 donor site (p = 0.0007; odds ratio =
2.46). The p value remained significant after correction for multiple
testing (p = 0.0062). In postmortem human cerebral cortical tissue, 2 of
the splice variants that encode transmembrane NRXN3 isoforms were
expressed at significantly lower levels in individuals with the
addiction-associated T allele of dbSNP rs8019381 than in CC homozygotes.
The data suggested that NRXN3 haplotypes that alter expression of
specific NRXN3 isoforms may play a role in genetic vulnerabilities to
alcohol dependence.

- Association with the SLC6A4 Gene on Chromosome 17q

Feinn et al. (2005) conducted a metaanalysis of the association of the
functional serotonin transporter promoter polymorphism (SLC6A4;
182138.0001) on chromosome 17q with alcohol dependence. The metaanalysis
was from data collected from 17 published studies including 3,489
alcoholics and 2,325 controls. The frequency of the short allele was
significantly associated with alcohol dependence (OR = 1.18, 95% CI =
1.03-1.33). A greater association with the S allele was seen among
individuals with alcohol dependence complicated by either a comorbid
psychiatric condition or an early-onset or more severe alcoholism
subtype (OR = 1.34, 95% CI = 1.11-1.63).

Following up on a study by Herman et al. (2003) that showed an
association between the SLC6A4 short form of the promoter polymorphism
and alcohol consumption in a college population, Munafo et al. (2005)
studied 755 individuals, aged 33 to 73 years, who were recruited from
general practices in the U.K. as part of a study of genetic associations
with smoking cessation. Subjects were assessed for age, gender, body
mass index, weekly alcohol consumption, ethnicity, and smoking habits.
Individuals who were nondrinkers were excluded from the study.
Genotyping was done for SLC6A4 long and short promoter polymorphisms.
The short allele was significantly associated with increased alcohol
consumption (p = 0.03). There was suggestive evidence of a genotype-sex
interaction (p = 0.04). Post hoc analysis indicated higher alcohol
consumption in men with one or more copies of the short allele, whereas
consumption in women was highest among heterozygotes compared to both
homozygote groups.

- Association with the COMT Gene on Chromosome 22q11

The enzyme catechol-O-methyltransferase (COMT; 116790), encoded by a
gene on chromosome 22q11, has a crucial role in the metabolism of
dopamine. Lachman et al. (1996) suggested that a common functional
genetic polymorphism in the COMT gene, which results in 3- to 4-fold
difference in COMT enzyme activity, may contribute to the etiology of
mental disorders such as bipolar disorder and alcoholism. Since
ethanol-induced euphoria is associated with the rapid release of
dopamine in limbic areas, it was considered conceivable that subjects
who inherited the allele encoding the low activity COMT variant would
have a relatively low dopamine inactivation rate, and therefore would be
more vulnerable to the development of ethanol dependence. In 2 Finnish
populations of type 1 (late-onset) alcoholics, Tiihonen et al. (1999)
found a markedly higher frequency of the low activity allele (L). They
estimated that the population etiologic (attributable) fraction for the
LL genotype in alcoholism was as high as 13.3%.

- Association with Opioid Receptor Genes

Zhang et al. (2008) genotyped 11 SNPs in the OPRD1 gene (165195) in
1,063 European Americans, including 620 with substance dependence, 557
with alcohol dependence, 225 with cocaine dependence, 111 with opioid
dependence (610064), and 443 controls. Although individual SNPs in
general did not show significant associations after multiple
corrections, haplotype analysis showed that a 6-SNP haplotype, which
harbors the G allele of 80G-T (dbSNP rs1042114) and the C allele of
921C-T (dbSNP rs2234918), was significantly associated with alcohol
dependence (p = 0.002) and opioid dependence (p less than 0.001). This
haplotype yielded odds ratios of 6.43 for alcohol dependence and 50.57
for opioid dependence.

In a study of 327 primarily European American individuals with alcohol
dependence and 358 controls, Zhang et al. (2008) found that a specific
haplotype defined by 7 SNPs in the OPRK1 gene (165196) was significantly
more common in those with alcohol dependence compared to controls (25.4%
versus 18.6%, p = 0.004). However, there was no significant differences
in allele, genotype, or global haplotype frequency distributions between
cases and controls.

Edenberg et al. (2008) identified an 841-bp insertion/11-bp deletion
(indel) polymorphism in the 5-prime untranslated region of the OPRK1
gene that was characterized by a net addition of 830 bp located 1986 bp
upstream of the translation start site. Transient transfection studies
showed that this upstream region was a promoter and that the presence of
the indel polymorphism reduced transcriptional activity by about 50%.
Genotyping studies of 1,914 individuals from 219 multiplex
alcohol-dependent families of European American descent showed a
significant association between presence of the indel polymorphism and
increased risk for alcoholism (p = 0.01).

ANIMAL MODEL

Liang et al. (2003) demonstrated that in alcohol-preferring and
alcohol-nonpreferring rats, a polymorphism in the alpha-synuclein gene
(SNCA; 163890) maps to the same location as a QTL for alcohol
preference.

In a rat operant ethanol self-administration model, Carnicella et al.
(2008) found that GDNF (600837) infusion resulted in rapid and
dose-dependent reduction in ethanol, but not sucrose,
self-administration. A GDNF-mediated decrease in ethanol consumption
(see 103780) was also observed in rats with a history of high voluntary
ethanol intake. The action of GDNF on ethanol consumption was specific
to the ventral tegmental area (VTA), since infusion into the substantia
nigra did not affect responses to ethanol. GDNF administration activated
the MAPK (176948) signaling pathway in the VTA, and inhibition of the
MAPK pathway in the VTA blocked reduction of ethanol self-administration
by GDNF. Carnicella et al. (2008) suggested that GDNF, via activation of
the MAPK pathway, is a fast-acting selective agent to reduce the
motivation to consume and seek alcohol.

*FIELD* SA
Nakamura et al. (1999); Propping et al. (1981)
*FIELD* RF
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32. Lachman, H. M.; Papolos, D. F.; Saito, T.; Yu, Y. M.; Szumlanski,
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37. Luo, X.; Kranzler, H. R.; Zuo, L.; Wang, S.; Blumberg, H. P.;
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with self report alcohol reactions, consumption and dependence: an
integrated analysis. Hum. Molec. Genet. 18: 580-593, 2009.

39. Munafo, M. R.; Lingford-Hughes, A. R.; Johnstone, E. C.; Walton,
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40. Nakamura, T.; Matsushita, S.; Nishiguchi, N.; Kimura, M.; Yoshino,
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2008.

*FIELD* CS

Neuro:
Alcoholism

Misc:
25 to 50% lifetime risk for sons and brothers of severely alcoholic
men

Inheritance:
Probably multifactorial, genetically influenced

*FIELD* CN
Cassandra L. Kniffin - updated: 9/11/2013
George E. Tiller - updated: 8/7/2013
Cassandra L. Kniffin - updated: 4/23/2010
Cassandra L. Kniffin - updated: 1/13/2010
Cassandra L. Kniffin - updated: 12/8/2009
George E. Tiller - updated: 11/23/2009
Cassandra L. Kniffin - updated: 10/27/2009
George E. Tiller - updated: 10/15/2009
Cassandra L. Kniffin - updated: 9/14/2009
Cassandra L. Kniffin - updated: 9/2/2009
Cassandra L. Kniffin - updated: 6/30/2009
Cassandra L. Kniffin - updated: 4/30/2009
George E. Tiller - updated: 1/12/2009
George E. Tiller - updated: 4/29/2008
Ada Hamosh - updated: 4/1/2008
George E. Tiller - updated: 1/16/2007
John Logan Black, III - updated: 11/9/2006
John Logan Black, III - updated: 4/6/2006
Victor A. McKusick - updated: 12/29/2005
John Logan Black, III - updated: 12/6/2005
Marla J. F. O'Neill - updated: 10/6/2005
John Logan Black, III - updated: 7/26/2005
John Logan Black, III - updated: 7/22/2005
John Logan Black, III - updated: 6/9/2005
Victor A. McKusick - updated: 6/10/2003
John Logan Black, III - updated: 11/15/2002
Victor A. McKusick - updated: 1/24/2001
Victor A. McKusick - updated: 8/4/1999
Victor A. McKusick - updated: 2/26/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
tpirozzi: 09/12/2013
ckniffin: 9/11/2013
alopez: 8/7/2013
terry: 11/15/2010
wwang: 8/4/2010
wwang: 7/27/2010
wwang: 6/21/2010
terry: 5/26/2010
wwang: 5/20/2010
wwang: 5/12/2010
ckniffin: 4/23/2010
wwang: 1/27/2010
ckniffin: 1/13/2010
wwang: 1/5/2010
ckniffin: 12/8/2009
wwang: 11/23/2009
wwang: 11/20/2009
ckniffin: 10/27/2009
wwang: 10/20/2009
terry: 10/15/2009
wwang: 10/6/2009
ckniffin: 9/14/2009
wwang: 9/10/2009
ckniffin: 9/2/2009
wwang: 7/24/2009
ckniffin: 6/30/2009
terry: 6/3/2009
wwang: 5/19/2009
ckniffin: 4/30/2009
wwang: 1/12/2009
wwang: 5/1/2008
terry: 4/29/2008
carol: 4/2/2008
terry: 4/1/2008
joanna: 1/25/2007
wwang: 1/24/2007
terry: 1/16/2007
carol: 11/10/2006
terry: 11/9/2006
carol: 4/7/2006
terry: 4/6/2006
carol: 4/4/2006
ckniffin: 1/6/2006
alopez: 12/30/2005
terry: 12/29/2005
carol: 12/6/2005
wwang: 10/20/2005
terry: 10/6/2005
wwang: 8/10/2005
terry: 8/8/2005
carol: 7/28/2005
terry: 7/26/2005
carol: 7/25/2005
terry: 7/22/2005
carol: 7/22/2005
terry: 6/9/2005
alopez: 9/24/2004
alopez: 9/23/2004
tkritzer: 7/8/2004
terry: 6/2/2004
terry: 8/15/2003
tkritzer: 6/17/2003
terry: 6/10/2003
carol: 11/15/2002
cwells: 1/26/2001
terry: 1/24/2001
jlewis: 8/17/1999
terry: 8/4/1999
carol: 2/27/1999
terry: 2/26/1999
mimadm: 4/14/1994
carol: 4/6/1994
supermim: 3/16/1992
carol: 1/10/1991
carol: 6/4/1990
carol: 6/1/1990

MIM 116790
*RECORD*
*FIELD* NO
116790
*FIELD* TI
+116790 CATECHOL-O-METHYLTRANSFERASE; COMT
CATECHOL-O-METHYLTRANSFERASE ACTIVITY, LOW, IN RED CELLS, INCLUDED
read more*FIELD* TX

DESCRIPTION

Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is one of the major
mammalian enzymes involved in the metabolic degradation of
catecholamines (summary by Gogos et al., 1998). COMT catalyzes the
transfer of a methyl group from S-adenosyl-methionine (SAM) to a
hydroxyl group on a catechol nucleus (e.g., dopamine, norepinephrine, or
catechol estrogen) (summary by Chen et al., 2004).

CLONING

Lundstrom et al. (1991) isolated cDNA clones for COMT from a human
placenta cDNA library using synthetic oligonucleotides as probes. The
clones contained an open reading frame that potentially coded for a
24.4-kD polypeptide, presumably corresponding to the cytoplasmic form of
COMT. DNA analysis suggested that the human, as well as the rat, dog,
and monkey, has 1 gene for COMT.

MAPPING

Wilson et al. (1984) excluded tight and close linkage of COMT with 21
and 15 loci, respectively. A lod score of 1.27 at theta = 0.1 was found
between COMT and phosphogluconate dehydrogenase (PGD; 172200), which is
on chromosome 1.

In studies of mouse-human cell hybrids with a method permitting direct
detection of COMT isozymes in autoradiozymograms, Brahe et al. (1986)
located the COMT gene on human chromosome 22. By study of DNAs from a
panel of human-hamster somatic cell hybrid lines, Grossman et al. (1991,
1992) mapped COMT to 22q11.1-q11.2. Winqvist et al. (1991) assigned COMT
to 22q11.2 by means of Southern blot analysis of somatic cell hybrids
and chromosomal in situ hybridization. They concluded that COMT is
located proximal to the breakpoint cluster region (BCR) involved in
chronic myeloid leukemia (151410). Bucan et al. (1993) mapped the
homologous murine gene to chromosome 16, where, as in the human, it is
closely linked to the lambda light chain genes.

During experiments aimed at building a contiguous group of YACs spanning
22q11, Dunham et al. (1992) found that the HP500 sequence often deleted
in the velocardiofacial syndrome (VCFS; 192430) was located within the
same 450-kb YAC as the COMT gene. They raised the question of whether
low COMT might be responsible for psychotic illness, which is a feature
of the VCF syndrome in adolescents and adults (Shprintzen et al., 1992).

BIOCHEMICAL FEATURES

Gustavson et al. (1973, 1982) reported that COMT activity was about 40%
higher in Down syndrome children than in normal controls. They
attributed this to dosage effect owing to a presumed location of the
COMT gene on chromosome 21. Brahe et al. (1986) studied the expression
of human COMT in interspecies somatic cell hybrids and found 27%
discordance between human chromosome 21 and human COMT, suggesting that
an assignment of the human COMT gene to chromosome 21 was very unlikely.

MOLECULAR GENETICS

- COMT Activity Polymorphism

Catechol-O-methyltransferase catalyzes the transfer of a methyl group
from S-adenosylmethionine to catecholamines, including the
neurotransmitters dopamine, epinephrine, and norepinephrine. This
O-methylation results in one of the major degradative pathways of the
catecholamine transmitters. In addition to its role in the metabolism of
endogenous substances, COMT is important in the metabolism of catechol
drugs used in the treatment of hypertension, asthma, and Parkinson
disease. In blood COMT is found mainly in erythrocytes; in leukocytes it
exhibits low activity. Weinshilboum and Raymond (1977) found bimodality
for red cell catechol-O-methyltransferase activity. Of a randomly
selected population, 23% had low activity. Segregation analysis of
family data suggested that low activity is recessive. Scanlon et al.
(1979) found that homozygotes have a thermolabile enzyme. Thus, the site
of the low COMT mutation is presumably the structural locus. Levitt and
Baron (1981) confirmed the bimodality of human erythrocyte COMT. They
further showed thermolability of the enzyme in 'low COMT' samples,
suggesting a structural alteration in the enzyme. Autosomal codominant
inheritance of the gene coding for erythrocyte COMT activity was adduced
by Floderus and Wetterberg (1981) and by Weinshilboum and Dunnette
(1981). Gershon and Goldin (1981) concluded that codominant inheritance
was consistent with the family data. Spielman and Weinshilboum (1981)
suggested that the inheritance of red cell COMT is intermediate, or
codominant, there being 3 phenotypes corresponding to the 3 genotypes in
a 2-allele system. The COMT of persons with low enzyme activity is more
thermolabile than that of persons with high activity.

- Susceptibility to Obsessive-Compulsive Disorder

Karayiorgou et al. (1997, 1999) found an association between
obsessive-compulsive disorder (OCD; 164230) and COMT; the homozygous low
activity genotype of the COMT gene was associated with risk for OCD in
males. Alsobrook et al. (2002) used a family-based genetic design in
haplotype relative risk (HRR) and transmission disequilibrium test (TDT)
analyses of the association between OCD and COMT. Fifty-six OCD probands
and their parents were genotyped for the COMT locus. Analysis of allele
and genotype frequencies between the proband genotypes and the control
(parental nontransmitted) genotypes failed to replicate the previous
finding of gender divergence and gave no evidence of overall
association; furthermore, no linkage was detected by TDT. However,
further analysis of the COMT allele frequencies by proband gender gave
evidence of a mildly significant association with the low activity COMT
allele in female probands (P = 0.049), but not in male probands.

- Susceptibility to Schizophrenia

The COMT gene is a strong candidate for schizophrenia susceptibility
(see 181500), owing to the role of COMT in dopamine metabolism and the
location of the gene within the deleted region in VCFS, a disorder
associated with high rates of schizophrenia. Shifman et al. (2002) found
a highly significant association between schizophrenia and a COMT
haplotype in a large case-control sample in Ashkenazi Jews. In addition
to the functional val158-to-met polymorphism (116790.0001; dbSNP
rs4680), this haplotype included 2 noncoding SNPs at either end of the
COMT gene (dbSNP rs737865 and dbSNP rs165599). With this background
information, Bray et al. (2003) postulated that the COMT susceptibility
haplotype is associated with low COMT expression. To test their
hypothesis, they applied quantitative measures of allele-specific
expression using mRNA from human brain. They demonstrated that COMT is
subject to allelic differences in expression in human brain and that the
COMT haplotype implicated in schizophrenia by Shifman et al. (2002) is
associated with lower expression of COMT mRNA. They also showed that the
3-prime flanking region SNP that in the study of Shifman et al. (2002)
gave greatest evidence for association with schizophrenia is transcribed
in human brain and exhibits significant differences in allelic
expression, with lower relative expression of the associated allele.
They concluded that the haplotype implicated in schizophrenia
susceptibility is likely to exert its effect, directly or indirectly, by
downregulating COMT expression.

In 38 populations representing all major regions of the world, Palmatier
et al. (2004) studied the frequency of the schizophrenia-associated COMT
haplotype reported by Shifman et al. (2002) as well as a 7-site COMT
haplotype. Their results supported the relevance of the COMT P2 promoter
to schizophrenia. The population data showed that the
schizophrenia-associated haplotype varies significantly in frequency
around the world and has significant heterogeneity when other markers in
COMT are also considered.

Lee et al. (2005) screened for 17 known polymorphisms in the COMT gene
in 320 Korean patients with schizophrenia and 379 controls. They
identified a positive association of schizophrenia with a nonsynonymous
SNP (dbSNP rs6267) at codon 72/22 (membrane/soluble-bound form) causing
an ala-to-ser substitution (A72S; 116790.0002). Lee et al. (2005) showed
that the A72S substitution was correlated with reduced COMT enzyme
activity, and their results supported previous reports that the COMT
haplotypes implicated in schizophrenia are associated with low COMT
expression.

- Susceptibility to Anorexia Nervosa

Frisch et al. (2001) found an association between anorexia nervosa (AN;
606788) and the COMT val158 allele (V158M; 116790.0001) in a
family-based study of 51 Israeli-Jewish AN trios. Gabrovsek et al.
(2004) could not replicate this finding in a combined sample of 372
European AN families, suggesting that the findings of Frisch et al.
(2001) were specific to a particular population and that val158 is in
linkage disequilibrium with other molecular variations in the COMT gene,
or its vicinity, which were the direct cause of genetic susceptibility
to anorexia nervosa. Michaelovsky et al. (2005) studied 85
Israeli-Jewish AN trios, including the original sample of Frisch et al.
(2001), comprising 66 anorexia nervosa restricting (AN-R) and 19
binge-eating/purging patients. They performed a family-based TDT
analysis for 7 SNPs in the COMT-ARVCF (602269) region including the
V158M polymorphism. TDT analysis of 5-SNP haplotypes in the AN-R group
revealed overall statistically significant transmission disequilibrium
for 'haplotype B' (COMT 186C, 408G, 472G [val158] and ARVCF 659C[pro220]
and 524T[val175]) (P less than 0.001), while 'haplotype A' (COMT 186T,
408C, 472A[met158] and ARVCF 659T[leu220] and 524C[ala175]) was
preferentially not transmitted (P = 0.01). Haplotype B was associated
with increased risk (RR of 3.38), while haplotype A exhibited a
protective effect (RR of 0.40) for AN-R. Preferential transmission of
the risk alleles and haplotypes from parents was mostly contributed by
fathers.

- Associations Pending Confirmation

Sweet et al. (2005) conducted a study to determine if COMT genetic
variation was associated with a risk of psychosis in Alzheimer disease
(AD; see 114300). The study included a case-control sample of 373
individuals diagnosed with AD with or without psychosis. Subjects were
characterized for alleles at 3 loci previously associated with
schizophrenia, dbSNP rs737865, dbSNP rs4680, and dbSNP rs165599, and for
a C/T transition adjacent to an estrogen response element (ERE6) in the
COMT P2 promoter region. Single-locus and haplotype tests of association
were conducted. Logit models were used to examine independent and
interacting effects of alleles at the associated loci and all analyses
were stratified by sex. In female subjects, dbSNP rs4680 demonstrated a
modest association with AD plus psychosis; dbSNP rs737865 demonstrated a
trend towards an association. There was a highly significant association
of AD plus psychosis with a 4-locus haplotype, which resulted from
additive effects of alleles at dbSNP rs4680 and ERE6/dbSNP rs737865 (the
latter were in linkage disequilibrium). In male subjects, no
single-locus test was significant, although a strong association between
AD with psychosis and the 4-locus haplotype was observed. That
association appeared to result from interaction of the ERE6/dbSNP
rs737865, dbSNP rs4680, dbSNP rs165599 loci. Genetic variation in COMT
was associated with AD plus psychosis and thus appears to contribute to
psychosis risk across disorders.

Three common haplotypes of the human COMT gene are divergent at 2
synonymous and 1 nonsynonymous position (Diatchenko et al., 2005). One
is dbSNP rs4633, which is either a C or T, but both code for a histidine
at amino acid 62; the other is dbSNP rs4818, which can be a G or C, but
both code for a leucine at nucleotide 136; the nonsynonymous haplotype
is represented by dbSNP rs4680, a met158-to-val change change
(116790.0001). Nackley et al. (2006) noted that the 3 common haplotypes
code for differences in COMT enzymatic activity and are associated with
pain sensitivity. Haplotypes divergent in synonymous changes exhibited
the largest difference in COMT enzymatic activity, due to a reduced
amount of translated protein. The major COMT haplotypes varied with
respect to mRNA local stem-loop structures, such that the most stable
structure was associated with the lowest protein levels and enzymatic
activity. Site-directed mutagenesis that eliminated the stable structure
restored the amount of translated protein. Nackley et al. (2006)
concluded that their data highlighted the functional significance of
synonymous variations and suggested the importance of haplotypes over
SNPs for analysis of genetic variations.

ANIMAL MODEL

Gogos et al. (1998) generated mice deficient for COMT. They measured the
basal concentrations of brain catecholamines in the striatum, frontal
cortex, and hypothalamus of adult male and female mutants and analyzed
locomotor activity, anxiety-like behaviors, sensorimotor gating, and
aggressive behavior. Mutant mice demonstrated sexually dimorphic and
region-specific changes of dopamine levels, notably in the frontal
cortex. Homozygous COMT-deficient female (but not male) mice displayed
impairment in emotional reactivity in the dark/light exploratory model
of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited
increased aggressive behavior. Gogos et al. (1998) concluded that their
results provided conclusive evidence for an important sex- and
region-specific contribution of COMT in the maintenance of steady-state
levels of catecholamines in the brain and suggested a role for COMT in
some aspects of emotional and social behavior in mice.

Kanasaki et al. (2008) showed that pregnant mice deficient in COMT
showed a preeclampsia-like phenotype resulting from absence of
2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is
elevated during the third trimester of normal human pregnancy.
Administration of 2-ME ameliorated all preeclampsia-like features
without toxicity in Comt -/- pregnant mice and suppressed placental
hypoxia, Hif1a (603348) expression, and soluble Flt1 (165070) elevation.
The levels of COMT and 2-ME were significantly lower in women with
severe preeclampsia. Kanasaki et al. (2008) suggested that Comt-null
mice may provide a model for preeclampsia and that 2-ME may serve as a
diagnostic marker as well as a therapeutic agent for preeclampsia.

Duplications of human chromosome 22q11.2 (608363) are associated with
elevated rates of mental retardation, autism, and many other behavioral
phenotypes. Suzuki et al. (2009) determined the developmental impact of
overexpression of an approximately 190-kb segment of human 22q11.2,
which includes the genes TXNRD2 (606448), COMT, and ARVCF (602269), on
behaviors in bacterial artificial chromosome (BAC) transgenic mice. BAC
transgenic mice and wildtype mice were tested for their cognitive
capacities, affect- and stress-related behaviors, and motor activity at
1 and 2 months of age. BAC transgenic mice approached a rewarded goal
faster (i.e., incentive learning), but were impaired in delayed rewarded
alternation during development. In contrast, BAC transgenic and wildtype
mice were indistinguishable in rewarded alternation without delays,
spontaneous alternation, prepulse inhibition, social interaction,
anxiety-, stress-, and fear-related behaviors, and motor activity.
Compared with wildtype mice, BAC transgenic mice had a 2-fold higher
level of COMT activity in the prefrontal cortex, striatum, and
hippocampus. Suzuki et al. (2009) suggested that overexpression of this
22q11.2 segment may enhance incentive learning and impair the prolonged
maintenance of working memory, but has no apparent affect on working
memory per se, affect- and stress-related behaviors, or motor capacity.
High copy numbers of this 22q11.2 segment may contribute to a highly
selective set of phenotypes in learning and cognition during
development.

*FIELD* AV
.0001
CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM
COMT, VAL158MET (dbSNP rs4680)

COMT inactivates catecholamines and catechol drugs such as L-DOPA.
Weinshilboum and Raymond (1977), Spielman and Weinshilboum (1981), and
others demonstrated that the level of COMT enzyme activity is
genetically polymorphic in human red blood cells (RBCs) and liver, with
a trimodal distribution of low, intermediate, and high levels of
activity. This genetic polymorphism results in a 3- to 4-fold difference
in COMT activity in RBCs and liver. Segregation analysis of data from
family studies demonstrated that the pattern of inheritance is
consistent with the presence of autosomal codominant alleles. The
polymorphism was also associated with individual variation in COMT
thermal instability. Lachman et al. (1996) showed that this polymorphism
is due to a G-to-A transition at codon 158 of the COMT gene, resulting
in a valine-to-methionine (V158M) substitution. The 2 alleles could be
identified with a PCR-based restriction fragment length polymorphism
analysis using the restriction enzyme NlaIII.

Lachman et al. (1996) studied patients with velocardiofacial syndrome
(VCFS; 192430), a relatively common congenital disorder associated with
typical facial appearance, cleft palate, cardiac defects, and learning
disabilities. Most patients have an interstitial deletion on 22q11. In
addition to physical abnormalities, a variety of psychiatric illnesses
have been reported in patients with VCFS, including schizophrenia
(181500), bipolar disorder (125480), and attention deficit hyperactivity
disorder. The psychiatric manifestations of VCFS could be due to
haploinsufficiency of a gene or genes within 22q11, and since the COMT
gene maps to this region, it is a candidate. Homozygosity for 158met
leads to a 3- to 4-fold reduction in enzymatic activity, compared with
homozygosity for 158val. Lachman et al. (1996) reported that in the
population of patients with VCFS, there was an apparent association
between the low-activity allele, 158met, and the development of bipolar
spectrum disorder and, in particular, a rapid-cycling form.

Comorbid panic disorder may define a subtype of bipolar disorder and may
influence the strength of association between bipolar disorder and
candidate genes involved in monoamine neurotransmission. Rotondo et al.
(2002) studied the frequency of the V158M polymorphism, the 5-HTTLPR
polymorphism of the serotonin transporter SLC6A4 (182138.0001), and a
splice site polymorphism (IVS7+218C-A) of tryptophan hydroxylase (TPH;
191060) in a case-control association study of bipolar disorder patients
with or without lifetime panic disorder. They compared results from DNA
extracted from blood leukocytes of 111 unrelated subjects of Italian
descent meeting DSM-III-R criteria for bipolar disorder, including 49
with and 62 without comorbid lifetime panic disorder, with those of 127
healthy subjects. Relative to the comparison subjects, subjects with
bipolar disorder without panic disorder, but not those with comorbid
bipolar disorder and panic disorder, showed significantly higher
frequencies of the COMT met158 and the short 5-HTTLPR alleles. No
statistical significance was found between the bipolar disorder groups
and the TPH polymorphism. Rotondo et al. (2002) concluded that bipolar
disorder without panic disorder may represent a more homogeneous form of
illness and that variants of the COMT and SLC6A4 genes may influence
clinical features of bipolar disorder.

Graf et al. (2001) treated 5 patients with the 22q11.2 deletion
syndrome, the 158met polymorphism, and neuropsychiatric illness with a
trial of metyrosine. They suggested that the presence of the 158met
variant on the nondeleted allele, known to be associated with decreased
enzyme activity, leads to increased catecholamine levels and could
contribute to neuropsychiatric manifestations. Metyrosine, a competitive
inhibitor of tyrosine hydroxylase, lowers the concentration of
homovanillic acid, presumably by decreasing brain dopamine. Four of the
5 patients treated experienced subjective improvements in overall
well-being.

Hoda et al. (1996) found no relationship between this common
polymorphism and susceptibility to idiopathic Parkinson disease.

Syvanen et al. (1997) likewise demonstrated a val158-to-met change as
the basis for the high-activity thermostable and low-activity
thermolabile forms of the COMT gene. In the Finnish population, they
found that the 2 COMT alleles are equally distributed. No statistically
significant difference in the frequencies of the COMT alleles were found
when comparing the normal population with a sample of 158 Finnish
patients with Parkinson disease.

Alcoholism (103780) has been classified into 2 subtypes. Type 2
alcoholism is associated with early onset, high novelty seeking, and
impulsive antisocial behavior. Most alcoholics can be classified as type
1, which is characterized by late onset (over 25 years) and no prominent
antisocial behavior (Cloninger, 1995). In vivo brain imaging studies in
humans have indicated that a dysfunction in dopaminergic
neurotransmission occurs in type 1 but not type 2 alcoholics. Since COMT
has a crucial role in the metabolism of dopamine, it was suggested that
the common functional genetic polymorphism in the COMT gene, which
results in 3- to 4-fold difference in COMT enzyme activity (Lachman et
al., 1996; Syvanen et al., 1997), may contribute to the etiology of
alcoholism. Since ethanol-induced euphoria is associated with the rapid
release of dopamine in limbic areas, it was considered conceivable that
subjects who inherited the allele encoding the low-activity COMT variant
would have a relatively low dopamine inactivation rate, and therefore
would be more vulnerable to the development of ethanol dependence.
Tiihonen et al. (1999) tested this hypothesis among type 1 (late-onset)
alcoholics. Two independent Finnish populations were studied, 1 in Turku
(67) and 1 in Kuopio (56). The high (H)- and low (L)-activity COMT
genotype and allele frequencies were compared with previously published
data from Finnish blood donors and race- and gender-matched controls.
The frequency of the L allele was markedly higher among the patients in
both groups when compared with the general population. The L allele
frequency was significantly higher among alcoholics when compared with
controls (P = 0.009). The estimate for population etiologic
(attributable) fraction for the LL genotype in alcoholism was 13.3% (95%
CI = 2.3-25.7%).

Egan et al. (2001) examined the relationship of this COMT polymorphism
(which they referred to as VAL108/158MET), which accounts for a 4-fold
variation in enzyme activity and dopamine catabolism, with both
prefrontally mediated cognition and prefrontal cortical physiology. In
175 patients with schizophrenia, 219 unaffected sibs, and 55 controls,
COMT genotype was related in allele dosage fashion to performance on the
Wisconsin Card Sorting Test of executive cognition and explained 4% of
variance in frequency of perseverative errors. The load of the low
activity met allele predicted enhanced cognitive performance. Egan et
al. (2001) then examined the effect of COMT genotype on prefrontal
physiology during a working memory task in 3 separate subgroups assayed
with functional MRI. The met allele load consistently predicted a more
efficient physiologic response in prefrontal cortex. In transmission
disequilibrium test of 104 trios, Egan et al. (2001) found a significant
increase in transmission of the val allele to the schizophrenic
offspring. Egan et al. (2001) concluded that the COMT val allele,
because it increases prefrontal dopamine catabolism, impairs prefrontal
cognition and physiology and by this mechanism slightly increases risk
for schizophrenia.

Shifman et al. (2002) reported the results of a study of COMT as a
candidate gene for schizophrenia, using a large sample size (the largest
case-control study performed to that time); a relatively well-defined
and homogeneous population (Ashkenazi Jews); and a stepwise procedure in
which several single nucleotide polymorphisms (SNPs) were scanned in DNA
pools, followed by individual genotyping and haplotype analysis of the
relevant SNPs. They found a highly significant association between
schizophrenia and a COMT haplotype; P = 9.5 x 10(-8).

Glatt et al. (2003) evaluated the collective evidence for an association
between the val158/108met polymorphism (codon 158 of the membrane-bound
form; codon 108 of the soluble form) of the COMT gene and schizophrenia
by performing a separate metaanalysis of 14 case-control and 5
family-based studies published between 1996 and 2002. Overall, the
case-control studies showed no indication of an association between
either allele and schizophrenia, but the family-based studies found
modest evidence implicating the val allele in schizophrenia risk. Glatt
et al. (2003) concluded that the family-based studies might be more
accurate since this method avoids the pitfalls of population
stratification. They suggested that the val allele may be a small but
reliable risk factor for schizophrenia for people of European ancestry
but that its role in Asian populations remained unclear.

Fan et al. (2005) conducted a large-scale association study plus
metaanalysis of the COMT val/met polymorphism and risk of schizophrenia
in 862 patients and 928 healthy control subjects from a Han Chinese
population. No significant differences were found in allele or genotype
frequencies between patients and normal control subjects, although a
nonsignificant overrepresentation of the val allele in schizophrenia
patients (OR = 1.09, 95% CI = 0.94-1.26) was suggested. The metaanalysis
provided no significant evidence for an association between
schizophrenia and the val allele in Asian or European populations.

Malhotra et al. (2002) studied 73 healthy individuals who took the
Wisconsin Card Sorting Test and were genotyped for the val158-to-met
polymorphism. ANOVA analysis revealed that the met/met group made
significantly fewer perseverative errors than either the met/val group
(p = 0.02) or the val/val group (p = 0.02). There were no significant
differences between the performances of the met/val and val/val groups.
The findings provided evidence that reduced COMT function is associated
with improved cognitive performance.

To determine if the V158M polymorphism influences prefrontal cognitive
function and increases the risk for schizophrenia, Rosa et al. (2004)
genotyped 89 sib pairs discordant for psychosis for this polymorphism
and assessed the sib pairs with the Wisconsin Card Sorting Test. In
healthy sibs, a linear relationship was seen in which performance on the
Wisconsin Card Sorting Test was associated in an allele dosage fashion
with COMT genotype (val/val vs other genotypes, p = 0.007); however,
this association was not observed in patients with schizophrenia.
Furthermore, there was no evidence of genetic association with
psychosis.

In a case-control study of 320 Korean patients with schizophrenia and
379 controls, Lee et al. (2005) found that the val/met polymorphism was
not associated with an increased risk of schizophrenia (OR = 0.88, 95%
CI = 0.64-1.21, p = 0.43).

Tsai et al. (2006) studied the transmission of the COMT val/met
polymorphism in 223 trios consisting of Chinese patients with
schizophrenia and their biologic parents. Using the transmission
disequilibrium test, they found no significant difference between
transmitted and nontransmitted allele frequencies for this polymorphism.

To study the association of the COMT val/met polymorphism with
schizophrenia, Williams et al. (2005) studied 2,800 individuals
including nearly 1,200 individuals with schizophrenia from case-control
and family-based European association samples. No support was found for
the hypotheses that the polymorphism influences susceptibility to
schizophrenia in general or in Ashkenazi or Irish subjects.

Munafo et al. (2005) studied the association of the COMT val108/158met
allele with schizophrenia by conducting a metaanalysis of 18 studies
published between 1996 and 2003. When all studies were included in a
metaregression, there was evidence for a significant association of the
COMT val allele frequency with schizophrenia case status and a
significant main effect of ancestry. However, the interaction of the
COMT val allele frequency and ancestry was also significant. When Munafo
et al. (2005) included only studies that reported allele frequencies
that did not depart significantly from Hardy-Weinberg equilibrium among
controls, these effects were no longer significant. Thus, the results of
the metaanalysis did not support an association between the COMT val
allele and schizophrenia case status and did not indicate that an
association may be moderated by ancestry.

Woo et al. (2002) studied 51 patients meeting DSM-IV criteria for panic
disorder and 45 healthy comparison subjects for the V158M polymorphism.
The frequency of the met/met genotype was significantly higher in
patients with panic disorder than in healthy subjects (19.6% vs 2.2%).
Furthermore, panic disorder was significantly associated with the met
allele (38.2% vs 18.9%). Patients with panic disorder who had the
met/met genotype had a poorer treatment response than those with other
genotypes. Woo et al. (2002) concluded that COMT activity might be
related to susceptibility to panic disorder and treatment response to
medications.

Wu et al. (2001) analyzed 224 Taiwanese patients with Parkinson disease
(168600) for MAOB intron 13 G (309860) and COMT L (V158M) polymorphisms
and found that the MAOB G genotype (G in men, G/G in women) was
associated with a 2.07-fold increased relative risk for PD, an
association which was stronger for men than for women. Although COMT
polymorphism alone was not associated with an increased risk for PD,
when it was considered in conjunction with the MAOB G genotype, there
was a 2.4-fold increased relative risk for PD. In men, the combined
alleles, MAOB G and COMT L, increased the relative risk for PD to 7.24.
Wu et al. (2001) suggested that, in Taiwanese, the development of PD may
be related to the interaction of 2 or more genes involved in dopamine
metabolism.

The functional V158M variant represents an exon 4 SNP that is detected
as an NlaIII restriction site polymorphism. It is polymorphic in
populations around the world (Palmatier et al., 1999). DeMille et al.
(2002) described a 4-site haplotype spanning 28 kb and effectively
encompassing the COMT gene.

Avramopoulos et al. (2002) genotyped 379 healthy 18- to 24-year-old male
individuals who had completed the Perceptual Aberration Scale (PAS),
Schizotypal Personality Questionnaire (SPQ), and Aggression
Questionnaire (AQ). Self-reported schizotypy scores were significantly
related to the COMT val158-to-met polymorphism (P = 0.028 for the PAS
and P = 0.015 for the SPQ). Individuals homozygous for the high activity
allele showed the highest scores. No significant findings were seen
using the AQ.

Suicidal behavior is often correlated with other-directed aggression,
which is believed to be partially mediated by catecholaminergic
neurotransmission. Rujescu et al. (2003) examined the influence of the
V158M polymorphism on suicidal behavior and anger-related traits. By Taq
polymerase digestion of PCR products, they genotyped 149 German suicide
attempters and 328 German control subjects. There was no overall
difference in allele/genotype frequency between patients and control
subjects. However, the low activity L allele was overrepresented in
violent suicide attempters (62% vs 51%). LL carriers expressed their
anger more outwardly versus HH carriers who expressed it more inwardly,
and they reported more state anger, as assessed by the State-Trait Anger
Expression Inventory. Rujescu et al. (2003) interpreted these findings
as supporting the hypothesis that this functional polymorphism may
modify the phenotype of suicide attempts and anger-related traits.

Zubieta et al. (2003) examined the influence of the V158M polymorphism,
which affects the metabolism of catecholamines, on the modulation of
responses to sustained pain in humans. Individuals homozygous for the
M158 allele showed diminished regional mu-opioid system (see 600018)
responses to pain compared with heterozygotes. These effects were
accompanied by higher sensory and affective ratings of pain and a more
negative internal affective state. Opposite effects were observed in
V158 homozygotes. Zubieta et al. (2003) concluded that the COMT V158M
polymorphism influences the human experience of pain and may underlie
interindividual differences in the adaptation and responses to pain and
other stressful stimuli.

The clinical effects of amphetamine are quite variable, from positive
effects on mood and cognition in some individuals, to negative responses
in others, perhaps related to individual variations in monoaminergic and
monoamine system genes. Mattay et al. (2003) found that amphetamine
enhanced the efficiency of prefrontal cortex function assayed with
functional MRI during a working memory task in subjects with the high
enzyme activity val/val genotype, who presumably have relatively less
prefrontal synaptic dopamine. In contrast, in subjects with the low
activity met/met genotype who tend to have superior baseline prefrontal
function, the drug had no effect on cortical efficiency at
low-to-moderate working memory load and caused deterioration at high
working memory load. The data illustrated an application of functional
neuroimaging and extended basic evidence of an inverted-'U'
functional-response curve to increasing dopamine signaling in the
prefrontal cortex. Further, individuals with the met/met catechol
O-methyltransferase genotype appeared to be at increased risk for an
adverse response to amphetamine.

In COS-1 and HEK293 cells, Shield et al. (2004) transiently expressed
wildtype and thr52 and met108 variants of COMT. The thr52 variant had no
significant change in level of COMT activity, but there was a 40%
decrease in the level of activity in cells transfected with the met108
variant. The met108 variant displayed a 70 to 90% decrease in
immunoreactive protein when compared with wildtype, but there was no
significant change in the level of immunoreactive protein for thr52. A
significant decrease in the level of immunoreactive protein was also
found in hepatic biopsy samples from patients homozygous for the met108
allele. Shield et al. (2004) concluded that the decreased level of
activity of the met108 allele appeared to be due to a reduced COMT
protein level.

In a large sample (n = 108) of postmortem human prefrontal cortex
tissue, which expresses predominantly the membrane-bound isoform of
COMT, Chen et al. (2004) studied the effects of several
single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression
levels (using RT-PCR analysis), protein levels (using Western blot
analysis), and enzyme activity (using catechol methylation). They found
that the common coding SNP V158M significantly affected protein
abundance and enzyme activity but not mRNA expression levels, suggesting
that differences in protein integrity account for the difference in
enzyme activity between alleles. Using site-directed mutagenesis of
mouse COMT cDNA followed by in vitro translation, they found that the
conversion of leu at the homologous position into met or val
progressively and significantly diminished enzyme activity. Thus,
although Chen et al. (2004) could not exclude a more complex genetic
basis for functional effects of COMT, val158 appeared to be a
predominant factor that determines higher COMT activity in the
prefrontal cortex, which presumably leads to lower synaptic dopamine
levels and relatively deleterious prefrontal function.

Using multimodal neuroimaging techniques to analyze 24 healthy
individuals, Meyer-Lindenberg et al. (2005) found that 11 carriers of
the val108/158 allele had significantly higher midbrain F-DOPA uptake
rates compared to 13 homozygous met108/158 carriers, indicating
decreased dopamine synthesis in met carriers. During a working memory
challenge test, the 2 genotypes were associated with inverse differences
in regional blood flow in the prefrontal cortex as related to midbrain
F-DOPA uptake, reflecting greater cortical extracellular dopamine in met
homozygotes. The findings suggested a dopaminergic 'tuning' mechanism in
the prefrontal cortex during cognitive processing and indicated a link
between cortical and subcortical dopaminergic activity.

Thapar et al. (2005) noted that early-onset antisocial behavior
accompanied by ADHD is a clinically severe variant of antisocial
behavior with a poor outcome. In 240 British children with ADHD or
hyperkinetic disorder, they studied the V158M SNP and the effects of
birth weight, which is an environmentally influenced index. A
comprehensive standardized assessment including measures of antisocial
behavior and IQ was conducted. The val/val genotype (P = 0.002) and
lower birth weight (P = 0.002) were associated with increased symptoms
of conduct disorder and a significant gene-environment interaction (P =
0.006) was also confirmed.

Bruder et al. (2005) examined the relation of V158M genotype to
performance on a battery of working memory tests that assessed different
cognitive operations. A total of 4,002 healthy adults were tested for
working memory tasks: Spatial Delayed Response, Word Serial Position
Test, N-back, and Letter-Number Sequencing. A subsample of 246
individuals was tested on the Wisconsin Card Sorting Test.
Letter-Numbering Sequencing was the only working memory test that showed
expected differences with the met/met group showing the best performance
and the val/val group reporting the poorest performance. The met/met
group also performed better than the val/val group on the Wisconsin Card
Sorting Test. Bruder et al. (2005) concluded that COMT genotype was not
associated with performance on tests measuring simple storage,
maintenance of temporal order, or updating of information in working
memory but was associated with higher-order components of processing.

Baker et al. (2005) studied 2 hypotheses: first, that individuals with
22q11 deletion syndrome (see 188400 and 192430) would manifest specific
cognitive and neurophysiologic abnormalities in common with individuals
at high risk for schizophrenia in the general population; and second,
that the COMT val108/158met polymorphism would modify the severity of
endophenotypic features. Adolescents and young adults with 22q11
deletion syndrome, aged 13-21, were compared with age- and IQ-matched
control subjects on measures that were associated with risk for
idiopathic schizophrenia. These individuals displayed poorer verbal
working memory and expressive language performance than control
subjects. Auditory mismatch negativity event-related potentials were
reduced at frontal electrodes but intact at temporal sites. The presence
of the COMT val108/158met allele on the single intact chromosome 22 was
associated with more marked auditory mismatch negativity amplitude
reduction and poorer neuropsychologic performance. Neither allele
influenced psychiatric symptoms.

Patients with DiGeorge syndrome (188400) are hemizygous for the COMT
gene. In a study of 21 nonpsychotic DiGeorge syndrome patients aged 7 to
16 years, Shashi et al. (2006) found that those carrying the met158
allele performed better on tests of general cognitive ability and on a
specific test of prefrontal cognition compared to those with the val158
allele. Glaser et al. (2006) tested measures of executive function, IQ,
and memory in 34 children and young adults with the 22q11.2
microdeletion (14 hemizygous for val158 and 30 for met158). No
significant differences were detected between met- and val-hemizygous
participants on measures of executive function. The groups did not
differ on full-scale, performance, and verbal IQ or on verbal and visual
memory. Glaser et al. (2006) suggested that either the COMT polymorphism
has a small effect on executive function in 22q11.2 deletion syndrome or
no effect exists at all.

Stolk et al. (2007) determined the genotype of the val158-to-met
polymorphism in 2,515 men and 3,554 women from the Rotterdam Study, a
population-based cohort study of individuals aged 55 and older. Male
carriers of the met158 allele had an increased risk for osteoporotic
fractures (hazard ratio = 1.6; 95% CI, 1.0-2.4) and for fragility
fractures (hazard ratio = 2.7; 95% CI, 1.3-5.9), with evidence for a
dominant effect. Adjustments for age, height, weight, and bone mineral
density (BMD) did not change the risk estimates. Stolk et al. (2007)
concluded that the COMT V158M polymorphism is associated with fracture
risk in elderly men, through a mechanism independent of BMD.

Zalsman et al. (2005) studied the relationship of MAOA promoter (u-VNTR;
309850.0002) and COMT missense (V158M) polymorphisms to CSF monoamine
metabolite levels in a psychiatric sample of 98 Caucasians who were
assessed for axis I and II diagnoses. CSF was obtained by lumbar
puncture and the relationships of the 2 polymorphisms to monoamine
metabolites (HVA, 5-HIAA, and MHPG) were examined. The higher-expressing
MAOA-uVNTR genotype was associated with higher CSF-HVA levels in males
(N = 46) (195.80 pmol/ml, SD = 61.64 vs 161.13, SD = 50.23,
respectively; p = 0.042). No association was found with the diagnosis.
The COMT V158M polymorphism was not associated with CSF monoamine
metabolite levels.

L-dopa, used to treat Parkinson disease (PD; 168600) is predominantly
metabolized to the inactive 3-O-methyldopa by COMT. Entacapone is a COMT
inhibitor that acts to prolong the half-life of L-dopa and yields
prolonged therapeutic benefits. The val158-to-met (V158M) polymorphism
in the COMT gene confers increased (val) or decreased (met) COMT
activity. In a randomized control trial of 33 PD patients, Corvol et al.
(2011) found that those homozygous for the high-activity val158 allele
had significantly increased COMT inhibition by entacapone and
significantly better bioavailability of and clinical response to L-dopa
compared to patients homozygous for the low-activity met158 allele. The
findings indicated that homozygosity for the val158 allele in PD
patients enhances the effect of entacapone on the pharmacodynamics and
pharmacokinetics of levodopa. The response to entacapone in heterozygous
patients was not studied.

.0002
SCHIZOPHRENIA, SUSCEPTIBILITY TO
COMT, ALA72SER

Lee et al. (2005) screened for 17 known polymorphisms in the COMT gene
in 320 Korean patients with schizophrenia and 379 controls. They
identified a positive association of schizophrenia with a nonsynonymous
SNP (dbSNP rs6267) at codon 72/22 (membrane/soluble-bound form) causing
an ala-to-ser substitution (A72S). With the ala/ala genotype as a
reference group, they found that the combined genotype (ala/ser and
ser/ser)-specific adjusted odds ratio was 1.82, suggesting 72ser as a
risk allele for schizophrenia. Lee et al. (2005) showed that the A72S
substitution was correlated with reduced COMT enzyme activity, and their
results supported previous reports that the COMT haplotypes implicated
in schizophrenia are associated with low COMT expression.

*FIELD* SA
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Weinshilboum (1979)
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disorder. Arch. Gen. Psychiat. 62: 1275-1278, 2005.

63. Tiihonen, J.; Hallikainen, T.; Lachman, H.; Saito, T.; Volavka,
J.; Kauhanen, J.; Salonen, J. T.; Ryynanen, O.-P.; Koulu, M.; Karvonen,
M. K.; Pohjalainen, T.; Syvalahti, E.; Hietala, J.: Association between
the functional variant of the catechol-O-methyltransferase (COMT)
gene and type 1 alcoholism. Molec. Psychiat. 4: 286-289, 1999.

64. Tsai, S.-J.; Hong, C.-J.; Hou, S.-J.; Yen, F.-C.: Lack of association
of catechol-O-methyltransferase gene val105/158met polymorphism with
schizophrenia: a family-based association study in a Chinese population.
(Letter) Molec. Psychiat. 11: 2-10, 2006.

65. Weinshilboum, R.; Dunnette, J.: Thermal stability and the biochemical
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66. Weinshilboum, R. M.: Catecholamine biochemical genetics in human
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67. Weinshilboum, R. M.; Raymond, F. A.: Inheritance of low erythrocyte
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68. Williams, H. J.; Glaser, B.; Williams, N. M.; Norton, N.; Zammit,
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69. Wilson, A. F.; Elston, R. C.; Siervogel, R. M.; Weinshilboum,
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70. Winqvist, R.; Lundstrom, K.; Salminen, M.; Laatikainen, M.; Ulmanen,
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71. Woo, J.-M.; Yoon, K.-S.; Yu, B.-H.: Catechol O-methyltransferase
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2002.

72. Wu, R. M.; Cheng, C. W.; Chen, K. H.; Lu, S. L.; Shan, D. E.;
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2001.

73. Zalsman, G.; Huang, Y.; Harkavy-Friedman, J. M.; Oquendo, M. A.;
Ellis, S. P.; Mann, J. J.: Relationship of MAO-A promoter (u-VNTR)
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in a psychiatric sample of Caucasians: a preliminary report. Am.
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74. Zubieta, J.-K.; Heitzeg, M. M.; Smith, Y. R.; Bueller, J. A.;
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val158-to-met genotype affects mu-opioid neurotransmitter responses
to a pain stressor. Science 299: 1240-1243, 2003.

*FIELD* CS

Metabolic:
Catecholamine transmitter degradation

Lab:
Catechol-O-methyltransferase deficiency

Inheritance:
Autosomal recessive (22q11.2)

*FIELD* CN
Cassandra L. Kniffin - updated: 3/24/2011
George E. Tiller - updated: 8/6/2010
Ada Hamosh - updated: 7/9/2008
John A. Phillips, III - updated: 3/24/2008
George E. Tiller - updated: 10/31/2007
Ada Hamosh - updated: 2/6/2007
John Logan Black, III - updated: 1/23/2007
John Logan Black, III - updated: 8/21/2006
John Logan Black, III - updated: 7/12/2006
John Logan Black, III - updated: 7/10/2006
John Logan Black, III - updated: 5/17/2006
John Logan Black, III - updated: 5/12/2006
Cassandra L. Kniffin - updated: 4/27/2006
Cassandra L. Kniffin - updated: 3/31/2006
John Logan Black, III - updated: 7/22/2005
John Logan Black, III - updated: 7/21/2005
Victor A. McKusick - updated: 3/31/2005
John Logan Black, III - updated: 2/28/2005
Victor A. McKusick - updated: 10/21/2004
John Logan Black, III - updated: 8/6/2004
John Logan Black, III - updated: 11/12/2003
John Logan Black, III - updated: 8/19/2003
John Logan Black, III - updated: 7/17/2003
Victor A. McKusick - updated: 7/9/2003
Victor A. McKusick - updated: 6/19/2003
Ada Hamosh - updated: 2/28/2003
Victor A. McKusick - updated: 1/8/2003
John Logan Black, III - updated: 12/10/2002
John Logan Black, III - updated: 11/21/2002
John Logan Black, III - updated: 11/8/2002
Cassandra L. Kniffin - updated: 7/29/2002
Cassandra L. Kniffin - updated: 5/24/2002
Ada Hamosh - updated: 4/30/2002
Victor A. McKusick - updated: 2/4/2002
Victor A. McKusick - updated: 11/18/1999
Victor A. McKusick - updated: 8/4/1999

*FIELD* CD
Victor A. McKusick: 1/7/1987

*FIELD* ED
wwang: 04/13/2011
ckniffin: 3/24/2011
carol: 10/20/2010
alopez: 10/19/2010
wwang: 8/10/2010
terry: 8/6/2010
wwang: 7/17/2008
terry: 7/9/2008
carol: 3/24/2008
alopez: 11/6/2007
terry: 10/31/2007
carol: 5/14/2007
alopez: 2/8/2007
terry: 2/6/2007
carol: 1/23/2007
carol: 8/21/2006
carol: 7/13/2006
terry: 7/12/2006
carol: 7/10/2006
wwang: 5/23/2006
terry: 5/17/2006
wwang: 5/17/2006
terry: 5/12/2006
wwang: 5/2/2006
ckniffin: 4/27/2006
wwang: 4/5/2006
ckniffin: 3/31/2006
carol: 7/26/2005
terry: 7/22/2005
carol: 7/21/2005
terry: 7/21/2005
carol: 5/23/2005
carol: 4/7/2005
carol: 4/6/2005
wwang: 4/4/2005
terry: 3/31/2005
carol: 3/31/2005
tkritzer: 2/28/2005
carol: 1/11/2005
alopez: 10/22/2004
terry: 10/21/2004
tkritzer: 8/6/2004
terry: 5/20/2004
mgross: 3/17/2004
carol: 11/18/2003
terry: 11/12/2003
cwells: 11/6/2003
carol: 8/20/2003
terry: 8/19/2003
terry: 8/15/2003
carol: 7/21/2003
terry: 7/17/2003
tkritzer: 7/15/2003
terry: 7/9/2003
alopez: 6/27/2003
terry: 6/19/2003
tkritzer: 5/8/2003
alopez: 3/3/2003
terry: 2/28/2003
carol: 2/27/2003
terry: 1/8/2003
carol: 12/10/2002
tkritzer: 12/10/2002
tkritzer: 12/4/2002
terry: 11/27/2002
carol: 11/21/2002
carol: 11/12/2002
carol: 11/8/2002
carol: 8/7/2002
ckniffin: 7/29/2002
carol: 5/24/2002
ckniffin: 5/23/2002
alopez: 5/1/2002
terry: 4/30/2002
terry: 3/11/2002
carol: 2/11/2002
terry: 2/4/2002
mcapotos: 7/25/2000
mgross: 12/7/1999
terry: 11/18/1999
jlewis: 8/17/1999
terry: 8/4/1999
alopez: 5/19/1997
alopez: 5/12/1997
mimadm: 6/25/1994
carol: 10/21/1993
carol: 9/20/1993
carol: 3/25/1993
carol: 12/7/1992
carol: 6/9/1992

RBCC Red Blood Cell Collection

Full text data of COMT