Important Variant Information for COMT

Submitted by: Amy E. Hodge (PharmGKB)
Reviewed by: Under Review
Submitted date: August 31, 2006

There is One Important Variant for COMT

COMT:Val108Met (COMT:Val158Met)

Gene HGNC Name:	COMT
Variant Summary:	Because COMT exists in membrane-bound and soluble forms, the numbering for the position of the polymorphism described here is different for the two forms. For the soluble form, the polymorphism is located at position 108, while for the membrane-bound form with its extra 50 N-terminal amino acids, this identical polymorphism is located at position 158. The Met allele is the low activity allele and is often referred to in the literature as the "L" allele; the Val allele is the high activity allele and is often referred to in the literature as the "H" allele. Schizophrenia The relationship between COMT genotype and schizophrenia is apparently complex. Some studies have shown that the Met allele is associated with susceptibility to schizophrenia [PMID: 9535125 (Japanese), 12372660]. One study on a white (Turkish) population showed a possible connection between the Met/Met (L/L) genotype and more severe clinical manifestations of schizophrenia [PMID: 11525417 (Turkish)], and another study showed that the low activity Met allele is associated with poorer performance on tests of cognitive function and decreased prefrontal cortex physiological responses in patients with schizophrenia or schizoaffective disorder [PMID: 11381111 (North American, European ancestry)]. This same study showed that the L allele is more frequently transmitted to siblings with schizophrenia. However, a study involving ethnic Chinese patients in Taiwan failed to show any association between V158 polymorphism and schizophrenia, although heterozygotes did have a later age at onset than Met/Met (L/L) individuals [PMID: 11150892 (Ethnic Chinese from Taiwan)]. They also saw no association with violent behaviors in this group. Other studies have also failed to show an association between COMT genotype and schizophrenia [PMID: 12815736 (Japanese), 14520117 (Caucasian-Finnish)]. Schizophrenia and Drug Response The Met (L) allele is associated with the requirement for a higher dose of neuroleptic and a tendency toward a higher rate of treatment-resistant schizophrenia [PMID: 12815736 (Japanese)]. Among a group of Finnish schizophrenics, non-responders to neuroleptics were more likely to possess a Met (L) allele, and additional risk of being a non-responder was seen if the patient possessed both a Met (L) allele as well as a low activity MAOA polymorphism, a particular NOTCH4 allele, or a high activity (D) ACE allele [PMID: 14520117 (Caucasian-Finnish), 15115916 (Caucasian-Finnish), 12729939 (Caucasian-Finnish)]. Other studies involving patients with schizophrenia or schizoaffective disorder who were treated with olanzapine or other antipsychotic drugs showed that the Met (L) allele is associated with improved working memory and prefrontal cortical physiology, as well as with an improvement in negative symptom ratings [PMID: 15522252, 15465976]. However, one study failed to show any association between COMT genotype and the response of schizophrenics to risperidone treatment [PMID: 14610521 (Japanese)], while another was unable to confirm some of the results from the Finnish study mentioned above [PMID: 16702905]. Other Psychiatric and Neurological Disorders The Met (L) allele is associated with panic disorder and homozygotes for this allele exhibit poorer treatment response [PMID: 12359690 (Korean)]. Anxiety-related personality traits associated with the Met (L) allele include increased anticipatory worry and fear of uncertainty [PMID: 12605099] and low extraversion and neuroticism [PMID: 15956988], though the latter association is seen only in women. The Met (L) allele was shown by one group to be associated with bipolar affective disorder [PMID: 9352569 (Han Chinese)], while another study indicated that the Met (L) allele is associated with depressive disorder but not bipolar disorder [PMID: 9631418 (Japanese)]. Another enticing study showed a potential association between the Met (L) allele and obsessive-compulsive disorder, but only in women [PMID: 11840516]. An analysis of COMT genotype and Parkinson's disease in a Taiwanese population indicated that the Met (L) allele is associated with Parkinson's Disease in women and in individuals with an earlier age of diagnosis [PMID: 12465073 (mostly Caucasian of European descent)]. In addition, the Met (L) allele is associated with narcolepsy in women and with a lower daily dose of modafinil in these patients, while the Val (H) allele is associated with poorer response to this drug [PMID: 11990384]. Other Drug Responses In one family-based haplotype analysis, the Val (H) allele was associated with heroin addiction [PMID: 11054766 (Israeli)], while another study showed that individuals with a Val (H) allele may be more likely to be multiple substance abusers [PMID: 9259381 (North American)]. Women carrying two Met (L) alleles are more likely to be ex-smokers than women who carry a Val (H) allele [PMID: 15900212]. These studies seem to indicate that Val (H) alleles may predispose individuals toward drug addiction, while the presence of Met (L) alleles may make it easier for people to successfully combat an addiction. One study on mu-opioids showed that Met (L) homozygosity is associated with decreased responses to pain and a decreased pain stimulus to reach similar levels of pain intensity [PMID: 12595695]. A study of morphine dosage in cancer patients indicated that Val (H) homozygotes received more morphine than did Met (L) homozygotes [PMID: 15927391 (Caucasian-Norway)]. Breast Cancer The Met (L) allele has been suggested to be associated with an increased risk for breast cancer [PMID: 15455371 (Taiwanese), 10519398 (Taiwanese)]. The suggested mechanism is that the Met (L) allele is associated with decreased expression of COMT protein resulting in a decrease in the formation of methylated, and thereby inactivated, catecholestrogens [PMID: 9407957, 10519398]. The details of a possible COMT/breast cancer association are still vague and the results of association studies have been contradictory [PMID: 11401913 (Finnish), 11434504 (Korean)]. The initial study reported an increased risk of breast cancer for the Met (L) allele only in post-menopausal women [PMID: 9407957], but a series of later studies reported an increased risk only in pre-menopausal women [PMID: 9605753, 14575568, 15388245, 15538046]. Studies have also shown that risk of breast cancer with a COMT Met (L) allele increases when high-risk alleles in other genes, such as UGT1A1, GSTT1, GSTM1, SOD2, CYP17A1, CYP1A1, and GSTP1 are also present [PMID: 9407957, 15455371 (Taiwanese), 10519398 (Taiwanese)]. Finally, several studies indicated that there is little or no association between COMT genotype and breast cancer, at least in the populations studied [PMID: 9855007, 16191465]. For tables with information on the relationship between COMT and breast cancer, see PMID: 10963624 and PMID: 14637391.
Key PubMed IDs:	9535125 (Japanese), 12372660, 11525417 (Turkish), 11381111 (North American, European ancestry), 11150892 (Ethnic Chinese from Taiwan), 12815736 (Japanese), 14520117 (Caucasian-Finnish), 15115916 (Caucasian-Finnish), 12729939 (Caucasian-Finnish), 15522252, 15465976, 14610521 (Japanese), 16702905, 12359690 (Korean), 12605099, 15956988, 9352569 (Han Chinese), 9631418 (Japanese), 11840516, 12465073 (mostly Caucasian of European descent), 11990384, 11054766 (Israeli), 9259381 (North American), 15900212, 12595695, 15927391 (Caucasian-Norway), 15455371 (Taiwanese), 10519398 (Taiwanese), 9407957, 11401913 (Finnish), 11434504 (Korean), 9605753, 16077979 (Japanese), 11706521 (Japanese), 12415427 (Turkish)
Genomic Variant & GenBank ID:	3103421 G>A on NT_011519
mRNA Variant & GenBank ID:	674 G>A on NM_000754
Protein Variant & GenBank ID:	158 Val>Met on NP_000745
dbSNP rs#:	rs4680
dSNP ss#:	ss35031502
GoldenPath Position:	Chr22: 18331271 (hg18)
Drugs/Substrates:	Heroin: 11054766 (Israeli) Modafinil: 11990384 Morphine: 15927391 (Caucasian-Norway) Neuroleptics: 12815736 (Japanese), 14520117 (Caucasian-Finnish), 15115916 (Caucasian-Finnish), 12729939 (Caucasian-Finnish), 16702905 Olanzapine or other Antipsychotics: 15522252, 15465976 Risperidone: 14610521 (Japanese)
Phenotypes/Diseases:	Anxiety Disorders: 12605099, 15956988 Bipolar Disorder: 9352569 (Han Chinese), 9631418 (Japanese) Breast Neoplasms: 15455371 (Taiwanese), 10519398 (Taiwanese), 9407957, 11401913 (Finnish), 11434504 (Korean), 9605753, 14575568, 15388245, 15538046, 9855007, 16191465, 10963624, 14637391 Depressive Disorder: 9631418 (Japanese) Narcolepsy: 11990384 Obsessive-Compulsive Disorder: 11840516 Pain: 12595695 Panic Disorder: 12359690 (Korean) Parkinson Disease: 12465073 (mostly Caucasian of European descent) Schizophrenia: 9535125 (Japanese), 12372660, 11525417 (Turkish), 11381111 (North American, European ancestry), 11150892 (Ethnic Chinese from Taiwan), 12815736 (Japanese), 14520117 (Caucasian-Finnish), 15115916 (Caucasian-Finnish), 12729939 (Caucasian-Finnish), 15522252, 15465976, 14610521 (Japanese), 16702905 Substance-Related Disorder: 11054766 (Israeli), 9259381 (North American), 15900212, 15927391 (Caucasian-Norway)
Phenotype Datasets:	S-COMT functional protein variants: describes in vitro enzymatic activity and immunoreactivity measurements for this and one other COMT variant

Frequency Table

Population Reported	Population OMB	Drug	Disease	% Val (H) Allele	% Met (L) Allele	Number of Chromosomes	Number of Samples	% Val/Val (H/H)	% Heterozygote	% Met/Met (L/L)	PMID	Notes
Disease Population Frequencies
Caucasian (Norway)	White	morphine	Neoplasms	44	56	414	207	21.2	46.4	32.4	15927391
Japanese	Asian	neuroleptics	Schizophrenia	66.5	33.5	200	100	41	51	8	12815736	frequencies did not differ significantly from control
Caucasian-Finnish	White	neuroleptics; total	Schizophrenia	48.4	51.6	188	94	27.6	41.5	30.9	14520117	for total schizophrenic population, frequencies did not differ significantly from the control
Caucasian-Finnish	White	neuroleptics; responders	Schizophrenia	55.8	44.2	86	43	27.9	55.8	16.3	14520117
Caucasian-Finnish	White	neuroleptics; non-responders	Schizophrenia	42.2	57.8	102	51	27.5	29.4	43.1	14520117
Japanese	Asian	risperidone	Schizophrenia	61	39	146	73	37	48	15	14610521
Ethnic Chinese from Taiwan	Asian		Schizophrenia	76.8	23.2	396	198	59.6	34.3	6.1	11150892
not reported	Unknown	olanzapine	Schizophrenia	55	45	60	30	26.7	56.7	16.6	15465976
not reported	Unknown	antipsychotics (olanzapine, perphenazine, ziprasidone, clozapine, risperidone, quetiapine, haloperidol, paroxetine, benztropine, valproic acid, trihexyphenidyl, lithium, sertraline)	Schizophrenia, Schizoaffective Disorder	53	47	40	20	25	55	20	15522252
North American, European ancestry	Unknown		Schizophrenia, Schizoaffective Disorder	60	40	350	175	35	49	16	11381111
Korean	Asian		Panic Disorder	61.8	38.2	102	51	43.1	37.3	19.6	12359690
Mixed (African American, Asian American, Hispanic American/Latino, Native American, Filipino American, European American, Other or missing)	Unknown		anxiety-related personality traits (extraversion, neuroticism)	59.5	40.5	994	497	37.2	44.5	18.3	15956988
European American only	Unknown		anxiety-related personality traits (extraversion, neuroticism)	51.6	48.4	492	246	26.8	49.6	23.6	15956988	subgroup from this study
Hispanic only	Unknown		anxiety-related personality traits (extraversion, neuroticism)	63.1	36.9	198	99	43.4	39.4	17.2	15956988	subgroup from this study
Israeli	White		Heroin Dependence	56.6	43.4	76	38	28.9	55.3	15.8	11054766
mostly Caucasian of European descent	White		Parkinson Disease	46	54	612	306	19.3	53.3	27.5	12465073
Taiwanese	Asian		Breast Neoplasms	71.5	28.5	938	469	50.5	42	7.5	15455371
Taiwanese	Asian		Breast Neoplasms	73.3	26.7	236	118	57.6	31.4	11.0	10519398
General Population Frequencies
Japanese	Asian			71	29	306	153	48	46	6	10459407; 9121699	Frequencies taken from PMID 10459407 without verification against original report
Japanese	Asian			64	36	300	150	39	51	10	10459407; 9535125	Frequencies taken from PMID 10459407 without verification against original report
Japanese	Asian			65	35	270	135	43	44	13	10459407; 9631418	Frequencies taken from PMID 10459407 without verification against original report
Japanese	Asian			68.7	31.3	402	201	43.8	49.8	6.5	12815736	control population for study
Chinese	Asian			75	25	124	62	60	31	9	10459407; 9159741	Frequencies taken from PMID 10459407 without verification against original report
Chinese	Asian			73	27	198	99	53	40	7	10459407; 9110105	Frequencies taken from PMID 10459407 without verification against original report
Han Chinese	Asian			82	18	196	98	67	30	3	10459407; 9352569	Frequencies taken from PMID 10459407 without verification against original report
Ethnic Chinese from Taiwan	Asian			73.1	26.9	376	188	52.1	42.0	5.9	11150892	control population for study
Taiwanese	Asian		Breast Neoplasms	74.5	25.5	1480	740	56.8	35.4	7.8	15455371	control population for study
Taiwanese	Asian		Breast Neoplasms	74.8	25.2	250	125	52.8	44.0	3.2	10519398	control population for study
Korean	Asian		Panic Disorder	81.1	18.9	90	45	64.5	33.3	2.2	12359690	control population for study
Israeli	White		Heroin Dependence	39.5	60.5	76	38	13.2	52.6	34.2	11054766	control population for study
North American	Unknown			60	40	174	87	34	51	15	10459407; 8886163	Frequencies taken from PMID 10459407 without verification against original report
North American	Unknown			44	56	248	124	18	51	31	10459407; 9259381	Frequencies taken from PMID 10459407 without verification against original report
North American Mixed European	Unknown			60	40	174	87	34	51	15	10459407; 9034544	Frequencies taken from PMID 10459407 without verification against original report
North American Mixed European	Unknown			60	40	174	87	34	51	15	10459407; 9264133	Frequencies taken from PMID 10459407 without verification against original report
North American Mixed European	Unknown			58	42	296	148	33	49	18	10459407; 9114031	Frequencies taken from PMID 10459407 without verification against original report
North American Mixed European	Unknown			51	49	258	129	24	54	22	10459407; 9532347	Frequencies taken from PMID 10459407 without verification against original report
North American, European ancestry	Unknown		Schizophrenia, Schizoaffective Disorder	54	46	110	55	27	55	18	11381111	control population for study
Caucasian	White			48	52	346	173	23	51	26	10459407; 8941353	Frequencies taken from PMID 10459407 without verification against original report
mostly Caucasian of European descent	White		Parkinson Disease	49	51	374	187	26.7	43.9	29.4	12465073	control population for study
European	Unknown			49	51	242	121	24	51	25	10459407; 9270905	Frequencies taken from PMID 10459407 without verification against original report
Finnish	White			42	58	152	76	18	46	36	10459407; 9110364	Frequencies taken from PMID 10459407 without verification against original report
Caucasian-Finnish	White			47.9	52.1	188	94	23.4	48.9	27.7	14520117	control population for study
United Kingdom	Unknown			47	53	156	78	26	42	32	10459407; 8561211	Frequencies taken from PMID 10459407 without verification against original report
Spanish	White			57	43	226	113	31	50	19	10459407; 8988970	Frequencies taken from PMID 10459407 without verification against original report

The PGRN is financially supported by grants from NIGMS, NHLBI, NHGRI, NIEHS, NCI, and NLM within the NIH, HHS. PharmGKB is managed at Stanford University. This work is supported by the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374). ©2001-2008 PharmGKB.