Rs4680

From SNPedia

rs4680 (Val158Met) is a well studied SNP in the COMT gene. spittoon summarizes them as

• rs4680(A) = Met, more exploratory, lower enzymatic activity
• rs4680(G) = Val, less exploratory, higher enzymatic activity

Roughly speaking, the predominant wisdom (known colloquially as the warrior/worrier hypothesis) posits that people with Val alleles have increased COMT activity and lower prefrontal extracellular dopamine compared with those with the Met substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.

Specific studies include:

rs4680, a functional Val/Met polymorphism, showed modest association with Irish familial schizophrenia. Haplotype A-G-A for SNPs rs737865-rs4680-rs165599 was preferentially transmitted to the affected subjects.

A study of 400 individuals reported that an increase in plasma total homocysteine (tHcy) of 10.4% (CI: 0.01-0.21, p=0.03) for associated with rs4680(A;A) homozygotes compared with rs4680(G;G) subjects. The (A;A) genotype was also more common, but statistically not that significantly, in venous thrombosis patients (OR 1.61, CI: 0.97-2.65], p=0.06) compared to control subjects.[PMID 18064318]

And from [PMID 15866551]: "Adolescent cannabis use was associated with increased risk of schizophreniform disorder in adulthood among Val/Val (i.e. rs4680(G;G)) individuals (OR = 10.9, 95% CI: 2.2–54.1) and, to a lesser extent, among Met/Val individuals (rs4680(A;G)); OR = 2.5, 95% CI: .78 – 8.2), but not among Met/Met (rs4680(A;A)) individuals (OR = 1.1, 95% CI: .21–5.4)."

Also potentially associated with schizophrenia

As part of a haplotype with rs4633, the (G) allele is also associated with endometrial cancer

In a study of 2 populations of breast cancer patients (2,000+ patients), increased risk was associated with rs4680(G;G) genotypes in both the Ontario [odds ratio 2.22, CI: 1.49-3.28] and Finland [OR 1.73, CI: 1.08-2.78] populations.[PMID 18194538]

spittoon The A version of rs4680 appears to boost working memory and cognitive function compared to G — but it also hampers emotional control.

[PMID 18704099] A study of 330 cocaine-dependent individuals, all of African descent, concluded that there was a slight (odds ratio 1.44, CI: 1.12-1.86, p = 0.014) association between the rs4680(A) allele, in other words the Met encoding allele, and cocaine dependence.

[PMID 18989660] A study of the antidepressant paroxetine found better response in Met/Met homozygotes, worse effects in Val/Val homozygotes and intermediate effects in heterozygotes. The effect became significant at the third week of treatment. Paroxetine daily dose was proportional to baseline severity, but did not influence outcome.

g2b2mh (A;A) subjects deploy more attentional focus when they realize they have made an error.

A meta-analysis of neuroimaging studies found a significant association between the COMT genotype and prefrontal activation; strong and opposing effects were found for executive cognition paradigms (favoring Met allele carriers) and emotional paradigms (favoring Val).[PMID 19417742]

[PMID 19071221] gray matter volume and interacts with rs2097603 related to extracellular dopamine

[PMID 19207030] rs6275/DRD2 and rs4680/COMT useful in predicting disease risk among schizophrenia patients

[PMID 19037200] rs4680(G;G) carriers deprived of sleep respond quite well to 2x 100mg modafinil in terms of improved vigor and well-being, and maintained baseline performance with respect to executive functioning, whereas rs4680(A;A) individuals barely responded to the drug at all.

[PMID 16878403] Met158 allele carriers had "a more focused response...during a working memory task." "The met158 allele seems to be beneficial during the performance of working memory and attention-related tasks, whereas the val158 allele appears to be advantageous during the processing of aversive emotional stimuli."

[PMID 15673663] "Increased limbic and prefrontal activation elicited by unpleasant stimuli in subjects with more met158 alleles might contribute to the observed lower emotional resilience against negative mood states."

[PMID 12595695] In response to pain Met/Met allele carriers showed greater "sensory and affective ratings of pain and a more negative internal affective state. Opposite effects were observed in val158 homozygotes. The COMT val158met polymorphism thus influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli."

[PMID 19367610] Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients

[PMID 19369177] Association of the 3' Region of COMT with Schizophrenia in Taiwan

[PMID 19417742] Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis

[PMID 19290789] Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment

[PMID 19077118] Genetic variants in COMT and neurocognitive impairment in families of patients with schizophrenia

[PMID 19474754] Antidepressive-drug-induced bodyweight gain is associated with polymorphisms in genes coding for COMT and TPH1

http://www.jneurosci.org/cgi/content/abstract/30/1/64 and blog discussion of data about rs4680 thinking about nothing in an fmri.

[PMID 19915868] Monoamine oxidase A gene polymorphisms and enzyme activity associated with risk of gout in Taiwan aborigines

[PMID 19946713] Attention-deficit/hyperactivity disorder phenotype is influenced by a functional catechol-O-methyltransferase variant

[PMID 20071037] Catechol-O-methyltransferase val108/158met genotype, major depressive disorder and response to selective serotonin reuptake inhibitors in major depressive disorder

[PMID 20070134] Association between COMT, PTSD, and increased smoking following hurricane exposure in an epidemiologic sample

[PMID 19690620] Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes

[PMID 20150638] Association of COMT Haplotypes and Breast Cancer Risk in Caucasian Women