Table 2. COMT rs4680† (val158met) association with disease in selected studies.
| Condition | Findings | Ref. |
|---|---|---|
| Executive function | ||
| Cognitive flexibility | The met/met genotype was associated with better performance on the WCST, compared with val/val genotype. However, this difference was not detected among patients with schizophrenia. During manic episodes, when dopamine levels are thought to be increased in the prefrontal cortex, val/val patients with BPD performed better on the WCST | [19,20] |
| Memory and attention | The met-allele was associated with enhanced working memory and better performance on attention-related tasks. Aging also influences cognition and among a biracial cohort of elders, COMT was associated with rate of cognitive decline, with the val-allele having a protective effect | [21,24] |
| Aggression | Although there was no main effect of COMT on aggression, in nonhuman primates, val/val macaques of higher rank exhibited higher rates of aggression. Conversely, rates of aggression decreased with rank among met/met and val/met animals | [25] |
| Stress response | Infants carrying the met allele had significantly higher negative emotionality and a greater cortisol response with repeated exposure to stress. The met-allele was associated with sensitivity to stressful events in childhood and adolescence and higher cortisol response to stress. Met-allele homozygotes were more susceptible to stress mindset interventions | [26–27] |
| Harm avoidance and novelty seeking | The val-allele was associated with more effective processing of aversive emotional stimuli, extraversion, novelty seeking. The met-allele was associated with harm avoidance which has an inverse relationship with novelty seeking | [21,28,29] |
| Psychiatric disease | ||
| Attention-deficit hyperactivity disorder | In a recent comprehensive meta-analysis of rs4680 genetic association studies across 15 psychiatric disorders and 363 datasets, the val-allele was more prevalent among ADHD cases versus controls | [30] |
| Substance-use disorder | In the same meta-analysis as above, the val-allele was more prevalent among SUD cases versus controls | [30] |
| Panic disorder | Among individuals of Asian ancestry, in the same meta-analysis as above, the val-allele was more prevalent among panic disorder cases versus controls | [30] |
| Bipolar disorder | BPD tended to be associated with the met-allele among individuals of Asian ancestry | [30] |
| Obsessive–compulsive disorder | OCD tended to be associated with the met-allele among males, in the same meta-analysis as above | [30] |
| Suicide | Although there is inconsistency across the many studies looking at COMT and suicide, a recent meta-analysis of 17 studies (3282 cases and 3774 controls) found the val-allele was a risk factor in males but protective in females | [31] |
| Major depressive disorder | The val/val genotype was significantly associated with reduced sadness scores and reduced disposition to depression. Although studies on COMT association with MDD are mixed, a recent large meta-analysis found no association overall or in gender subgroups | [32,33] |
| Neurological disease | ||
| Delirium | Perturbations in executive function can result in delirium which affects mainly attention, and dementia which affects mainly memory. Although COMT does not appear to directly influence delirium, it modified the known association between C-reactive protein (CRP), an acute phase reactant, and postoperative delirium | [34,35] |
| Functional pain disorders | A recent meta-analyses of COMT and functional pain disorders found that the low-activity met-allele was associated with fibromyalgia. An earlier meta-analysis also found that the met-allele was associated with fibromyalgia and widespread chronic pain, but not migraine headache or chronic musculoskeletal pain conditions | [36,37] |
| Chronic fatigue syndrome | Chronic fatigue syndrome patients were more likely to be homozygous for the met-allele compared with val-allele carriers | [38,39] |
| Pain | COMT low-activity haplotypes were associated with greater sensitivity to nociceptive, but lower sensitivity to neuropathic pain. Conversely, high-activity haplotypes were associated with lower sensitivity to nociceptive but greater sensitivity to neuropathic pain. In breast cancer survivors, pain sensitivity and fatigue was greater among met-allele homozygotes | [40,41] |
| Parkinson disease | COMT inhibitor drugs are used as adjunctive treatment for patients with Parkinson disease. Researchers have failed to find a clear association between COMT and Parkinson disease, but several studies have demonstrated COMT genotype modulation of prefrontal cortex dysfunction early in the course of Parkinson disease. Specifically, increasing numbers of met-alleles was associated with diminished performance on tasks that tested prefrontal cortex functions | [42–44] |
| Alzheimer disease | Similarly, although metabolism of dopamine and other catecholamines can influence Alzheimer disease, results of COMT association with the disease have yielded directionally inconsistent findings. Still, recent meta-analyses reported a COMT association with AD among Asians but not Caucasians | [45] |
| Autoimmune disease | COMT’s role in limiting the damaging effects of oxidative and emotional stress make its potential role in the etiology of auto-immune diseases plausible. Studies in psoriasis, narcolepsy and systemic lupus erythematosus suggest a link between COMT and autoimmune diseases | [46–47] |
| Cardiometabolic disease | ||
| Cardiometabolic disease risk factors | The COMT rs4680 high-activity val-allele, which is associated with lower levels of catecholamines, is consistently associated with lower cardiometabolic risk factors, including triglycerides, systolic blood pressure and hemoglobin A1c | [48–49] |
| Diabetes | The COMT val-allele was modestly protective from risk of Type II diabetes | [[50–51] |
| Cardiovascular disease | The val-allele was protective from risk of cardiovascular disease in several studies | [48,52,53] |
| Pre-eclampsia | The met-allele and a low-COMT activity haplotype were associated with recurrent pre-eclampsia. In murine models of pre-eclampsia, pre-eclampsia-like phenotypes in COMT-deficient pregnant mice were corrected with 2-methoxyestradiol treatment | [6] |
| Cancer | ||
| Invasive cancers | Although the met-allele is frequently associated with increased risk of cancers, there are as many studies with null or opposite effects. Consistent with this hypothesis, we recently demonstrated that COMT was associated with rates of invasive cancer in two large RCTs of vitamin E for cancer prevention | [4,54] |
†
The COMT rs4680 val-allele encodes a form of the enzyme which is 3–4× more active than the met-allele form.
ADHD: Attention-deficit hyperactivity disorder; BPD: Bipolar disorder; COMT: Catechol-O-methyltransferase; OCD: Obsessive-compulsive disorder; MDD: Major depressive disorder; RCT: Randomized controlled trial; SUD: Substance-use disorder; WCST: Wisconsin Card Sorting Test.