rs4680

rs4680 (Val158Met) is a well studied SNP in the COMT gene. The COMT gene codes for the COMT enzyme, which breaks down dopamine in the brain's prefrontal cortex. The wild-type allele is a (G), coding for a valine amino acid; the (A) substitution polymorphism changes the amino acid to a methionine. This alters the structure of the resultant enzyme such that its activity is only 25% of the wild type. As a result, A allele carriers have more dopamine in their prefrontal cortex, which may be responsible for many of the neuropsychological associations listed below. 23andMe blog summarizes the alleles at this SNP as *rs4680(A) = Worrier. Met, more exploratory, lower COMT enzymatic activity, therefore higher dopamine levels; lower pain threshold, enhanced vulnerability to stress, yet also more efficient at processing information under most conditions *rs4680(G) = Warrior. Val, less exploratory, higher COMT enzymatic activity, therefore lower dopamine levels; higher pain threshold, better stress resiliency, albeit with a modest reduction in executive cognition performance under most conditions Roughly speaking, the predominant wisdom (known colloquially as the warrior/worrier hypothesis; summary at ) 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. And from : "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. 23andMe blog The A version of rs4680 appears to boost working memory and cognitive function compared to G — but it also hampers emotional control. 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. 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). gray matter volume and interacts with rs2097603 related to extracellular dopamine rs6275/DRD2 and rs4680/COMT useful in predicting disease risk among schizophrenia patients 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. 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." "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." 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." Reports that ease of entering hypnosis correlates with number of rs4680(G) alleles. see gs226 for a report related to impulsiveness http://www.jneurosci.org/cgi/content/abstract/30/1/64 and blog discussion of data about rs4680 thinking about nothing in an fmri. Breast Cancer Risk Modifiers

A;A

Little or no response to modafinil. You are more difficult to hypnotise. Placebo is more effective http://www.nytimes.com/2013/02/10/magazine/why-can-some-kids-handle-pressure-while-others-fall-apart.html?ref=magazine&pagewanted=all

A;G

As is often the case with heterozygotes, shares many traits intermediately between the (A;A) and (G;G) homozygotes. Specific (A;G) findings include:

G;G

You have the VAL/VAL version of the SNP. It is able to perform better in a test where the optimal strategy changes. Placebo is less effective for you http://www.nytimes.com/2013/02/10/magazine/why-can-some-kids-handle-pressure-while-others-fall-apart.html