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60-477: 4XUE , 3A7E , 3BWM , 3BWY , 4PYI , 4PYJ , 4PYK , 4XUC , 4XUD 1312 12846 ENSG00000093010 ENSMUSG00000000326 P21964 O88587 NM_000754 NM_001135161 NM_001135162 NM_007310 NM_001362828 NM_001111062 NM_001111063 NM_007744 NP_000745 NP_001128633 NP_001128634 NP_009294 NP_001349757 NP_001104532 NP_001104533 NP_031770 Catechol- O -methyltransferase ( COMT ; EC 2.1.1.6 )

120-546: A family history , from which 5–10 percent can be attributed to a causative risk gene mutation , although harboring one of these mutations may not lead to the disease. As of 2024, around 90 genetic risk variants across 78 genomic loci have been identified with studies employing next-generation sequencing (NGS) to uncover detailed insights into these genetic factors. Notable risk genes include SNCA , LRRK2 , and VPS35 for autosomal dominant inheritance, and PRKN , PINK1 , and DJ1 for autosomal recessive inheritance. LRRK2

180-401: A methyl group to the catecholamine, which is donated by S-adenosyl methionine (SAM). Any compound having a catechol structure, like catecholestrogens and catechol-containing flavonoids, are substrates of COMT. Levodopa , a precursor of catecholamines, is an important substrate of COMT. COMT inhibitors, like entacapone , save levodopa from COMT and prolong the action of levodopa. Entacapone

240-433: A pleiotropic effect on emotional processing. Furthermore, the polymorphism has been shown to affect ratings of subjective well-being . When 621 women were measured with experience sample monitoring , which is similar to mood assessment as response to beeping watch, the met/met form confers double the subjective mental sensation of well-being from a wide variety of daily events. The ability to experience reward increased with

300-505: A clear sensorium . It might overlap with other psychiatric symptoms, making the diagnosis challenging. Impulse-control disorders (ICD) can be seen in approximately 19 percent of all patients and, in the context of PD, are grouped along with compulsive behavior and dopamine dysregulation syndrome (DDS) within the broader spectrum of impulsive and compulsive behaviors (ICB). They are characterized by impulsivity and difficulty to control impulsive urges and are positively correlated with

360-738: A direct role in neurodegeneration , while Lewy bodies are thought to serve as an indirect marker of disease progression. A vicious cycle linked to neurodegeneration involves oxidative stress , mitochondria, and neuroimmune function, particularly inflammation . Normal metabolism of dopamine tends to fail, leading to elevated levels of reactive oxygen species (ROS) which is cytotoxic and causes cellular damage to lipids , proteins , DNA , and especially mitochondria. Mitochondrial damage triggers neuroinflammatory responses via damage-associated molecular patterns (DAMPs), resulting in aggregation of neuromelanin , and therefore, fueling further neuroinflammation by activating microglia . Ferroptosis

420-545: A few contributing factors have been identified. Pathophysiology is characterized by progressively expanding nerve cell death originating in substantia nigra , a midbrain region that supplies dopamine to the basal ganglia , a system involved in voluntary motor control . The cause of this cell death is poorly understood but involves alpha-synuclein aggregation into Lewy bodies within the neurons . Other possible factors involve genetic and environmental mechanisms, medications, lifestyle, and previous conditions. Diagnosis

480-485: A major DNA damage -repair signaling kinase , and non-homologous end joining DNA repair pathway. Identifying environmental risk factors and causality is difficult due to the disease's often decade-long prodromal period. Most noteworthy environmental factors include pesticide exposure and contact with heavy metals. In particular, exposure to pesticides such as paraquat , rotenone , benomyl , and mancozeb causes one in five cases, implying an association with

540-459: A strong influence on reward experience in the flow of daily life. In one study participants with the met/met phenotype described an increase of positive affect twice as high in amplitude as participants with the Val/Val phenotype following very pleasant or pleasant events. One review found that those with Val/Val tended to be more extroverted, more novelty-seeking, and less neurotic than those with

600-506: Is ValMet . Others are rs737865 and rs165599 that have been studied, e.g., for association with personality traits , response to antidepressant medications, and psychosis risk associated with Alzheimer's disease . COMT has been studied as a potential gene in the pathogenesis of schizophrenia; however meta-analyses find no association between the risk of schizophrenia and a number of polymorphisms, including ValMet. A functional single-nucleotide polymorphism (a common normal variant) of

660-414: Is a widely used adjunct drug of levodopa therapy. When given with an inhibitor of dopa decarboxylase (carbidopa or benserazide), levodopa is optimally saved. This "triple therapy" is becoming a standard in the treatment of Parkinson's disease . Specific reactions catalyzed by COMT include: In the brain, COMT-dependent dopamine degradation is of particular importance in brain regions with low expression of

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720-413: Is associated with higher morbidity and mortality. Other autonomic-related symptoms include excessive sweating, urinary incontinence , and sexual dysfunction . Neuropsychiatric symptoms (NPS) are common and range from mild disturbances to severe impairment, comprising abnormalities in cognition, mood, behavior, or thought which can interfere with daily activities, reduce quality of life, and increase

780-403: Is caused by a distinct biomechanical process or if it is the manifestation of another cardinal sign of PD. Postural instability (PI) is typical in the later stages of the disease, leading to impaired balance and falls , and secondarily to bone fractures, thus, reduced mobility and quality of life. PI is absent in the initial stages and usually occurs 10–15 years after first diagnosis. Within

840-507: Is considered one of the primary contributing factors for nigrostriatal neuron death in PD. When overexpressed or misfolded , it can form clumps on axon terminals and other neuronal structures, particularly its typical locations: the cytoplasm , mitochondria and nucleus . These aggregates eventually lead to the formation of Lewy bodies . Their precursors, known as oligomers , along with initial deposits called pale bodies, are believed to play

900-502: Is estimated to be responsible for 1-2% of all cases of PD and 40% of familial cases. Additionally, mutations in the GBA1 gene, linked to Gaucher's disease , are found in 5–10 percent of PD cases. The GBA1 variant of genetic PD more commonly involves cognitive decline. Alpha-synuclein (aSyn), a protein encoded by SNCA gene , is thought to be primarily responsible Lewy body aggregation. ASyn activates ATM serine/threonine kinase ,

960-969: Is known to be present in up to 55 percent of PD patients. While it is responsible for most of paresthesia and pain in Parkingson Disease, its role in postural instability and motor impairment is poorly understood. Alterations in the autonomic nervous system , known as dysautonomia , are associated with a variety of symptoms such as gastrointestinal dysfunction , orthostatic hypotension , excessive sweating, or urinary incontinence. Gastrointestinal issues include constipation, impaired stomach emptying , immoderate production of saliva , and swallowing difficulty (prevalence up to 82 percent). Complications resulting from dysphagia include dehydration , malnutrition, weight loss, and aspiration pneumonia . All gastrointestinal features can be severe enough to cause discomfort, endanger health, and complicate disease management. Despite being related to each other,

1020-519: Is mainly based on signs and symptoms , usually motor-related, found via neurological examination , though medical imaging like neuromelanin MRI can support the diagnosis. Usual onset is in people over 60 years of age, of whom about one percent are affected. In those younger than 50, it is termed "early-onset PD". No cure is known; treatment aims to lessen symptoms. Initial treatment typically includes L-DOPA , MAO-B inhibitors , or dopamine agonists . As

1080-461: Is near-normal. Parkinson's disease (PD) is a neurodegenerative disease affecting both the central and peripheral nervous systems , characterized by the loss of dopamine -producing neurons in the substantia nigra region of the brain. It is classified as a synucleinopathy due to the abnormal accumulation of the protein alpha-synuclein , which aggregates into Lewy bodies within affected neurons. The loss of dopamine-producing neurons in

1140-466: Is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine , epinephrine , and norepinephrine ), catecholestrogens , and various drugs and substances having a catechol structure. In humans, catechol- O -methyltransferase protein is encoded by the COMT gene . Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As

1200-428: Is the most common presenting sign and may appear at rest as well as during intentional movement with a frequency between 4–6  hertz (cycles per second). PD tremor tends to occur in the hands, but can affect other parts of the body, such as legs, arms, tongue, or lips, as well. It is often described as " pill-rolling ", the tendency of the index finger and thumb to touch and perform a circular movement that reminds of

1260-575: The EMBL-EBI Enzyme Portal). Before the development of the EC number system, enzymes were named in an arbitrary fashion, and names like old yellow enzyme and malic enzyme that give little or no clue as to what reaction was catalyzed were in common use. Most of these names have fallen into disuse, though a few, especially proteolyic enzymes with very low specificity, such as pepsin and papain , are still used, as rational classification on

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1320-672: The autonomic or sensory nervous system, mood , behavior, sleep patterns, and cognition. Non-motor symptoms may precede the onset of motor symptoms by up to 20 years. These include constipation, anosmia , mood disorders , and REM sleep behavior disorder among others. In general, motor symptoms such as postural instability and gait abnormalities tend to appear as the disease progresses. Four motor symptoms are considered as cardinal signs in PD: tremor, bradykinesia, rigidity, and postural instability, collectively known as parkinsonism . However, other motor-associated symptoms are common. Tremor

1380-590: The dopaminergic system which plays a central role in motor control . Three major pathways connect the basal ganglia to other brain areas: direct, indirect, and hyperdirect pathway, all part of the cortico-basal ganglia-thalamo-cortical loop . The direct pathway projects from the neocortex to putamen or caudate nucleus of the striatum, which sends inhibitory GABAergic signals to substantia nigra pars reticulata (SNpr) and internal globus pallidus (GPi). This inhibition reduces GABAergic signaling to ventral lateral (VL) and ventral anterior (VA) nuclei of

1440-478: The thalamus , thereby promoting their projections to the motor cortex . The indirect pathway projects inhibition from striatum to external globus pallidus (GPe), reducing its GABAergic inhibition of the subthalamic nucleus , pars reticulata and internal globus pallidus. This reduction in inhibition allows the subthalamic nucleus to excite internal globus pallidus and pars reticulata, which in turn inhibit thalamic activity, thereby suppressing excitatory signals to

1500-452: The tripeptide aminopeptidases have the code "EC 3.4.11.4", whose components indicate the following groups of enzymes: NB:The enzyme classification number is different from the 'FORMAT NUMBER' Oxidation /reduction reactions; transfer of H and O atoms or electrons from one substance to another Similarity between enzymatic reactions can be calculated by using bond changes, reaction centres or substructure metrics (formerly EC-BLAST], now

1560-550: The Enzyme Commission was dissolved at that time, though its name lives on in the term EC Number . The current sixth edition, published by the International Union of Biochemistry and Molecular Biology in 1992 as the last version published as a printed book, contains 3196 different enzymes. Supplements 1-4 were published 1993–1999. Subsequent supplements have been published electronically, at the website of

1620-636: The Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing dopaminergic stimulation of the postsynaptic neuron. Given the preferential role of COMT in prefrontal dopamine degradation, the ValMet polymorphism is thought to exert its effects on cognition by modulating dopamine signaling in the frontal lobes . The gene variant has been shown to affect cognitive tasks broadly related to executive function , such as set shifting, response inhibition, abstract thought, and

1680-573: The Met/Met allele Temporomandibular joint dysfunction (TMD) does not appear to be a classic genetic disorder, however variations in the gene that codes for COMT have been suggested to be responsible for inheritance of a predisposition to develop TMD during life. COMT is the name given to the gene that codes for this enzyme. The O in the name stands for oxygen , not for ortho . COMT inhibitors include entacapone , tolcapone , opicapone , and nitecapone . All except nitecapone are used in

1740-621: The Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. In August 2018, the IUBMB modified the system by adding the top-level EC 7 category containing translocases. Parkinson%27s disease Parkinson's disease ( PD ), or simply Parkinson's , is a neurodegenerative disease of mainly the central nervous system that affects both the motor and non-motor systems of

1800-557: The acquisition of rules or task structure. Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia . It has been proposed that an inherited variant of COMT is one of the genetic factors that may predispose someone to developing schizophrenia later in life. A more recent study cast doubt on the proposed connection between this gene and any alleged casual effect of cannabis on schizophrenia development. A non-synonymous single-nucleotide polymorphism rs4680

1860-605: The basis of specificity has been very difficult. By the 1950s the chaos was becoming intolerable, and after Hoffman-Ostenhof and Dixon and Webb had proposed somewhat similar schemes for classifying enzyme-catalyzed reactions, the International Congress of Biochemistry in Brussels set up the Commission on Enzymes under the chairmanship of Malcolm Dixon in 1955. The first version was published in 1961, and

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1920-503: The body. The symptoms usually emerge slowly, and, as the disease progresses, non-motor symptoms become more common. Usually symptoms include tremors , slowness of movement , rigidity , and difficulty with balance , collectively known as parkinsonism . Parkinson's disease dementia , falls and neuropsychiatric problems such as sleep abnormalities , psychosis , mood swings , or behavioral changes may also arise in advanced stages. Most cases of Parkinson's disease are sporadic , but

1980-451: The characteristic reduced facial expression known as "masked face" or hypomimia . Rigidity , also referred to as rigor or "stiffness", is the increased resistance during passive mobilization of a limb affecting up to 89 percent of cases. It usually occurs after onset of tremor and bradykinesia on one or both sides of the body and can lead to muscle or joint pain as the disease progresses. As of 2024, it remains unclear whether rigidity

2040-478: The disease progresses, these medications become less effective and produce a side effect marked by involuntary muscle movements . Diet and certain forms of rehabilitation have shown some effectiveness at improving symptoms. Deep brain stimulation has been used to reduce severe motor symptoms when drugs are ineffective. There is little evidence for treatment of the non-movement-related symptoms, such as sleep disturbances and mood instability. The average life expectancy

2100-405: The disease. Neuronal cell death has been linked to noumerous mechanisms, with the most prominent being the misfolding and aggregation of alpha-synuclein , oxidative stress , neuroinflammation , ferroptosis , mitochondrial dysfunction , and gut dysbiosis. Alpha-synuclein (aSyn), a protein involved in synaptic vesicle trafficking , intracellular transport , and neurotransmitter release ,

2160-610: The early pharmaceutical technique of manually making pills. Despite it being the most noticeable sign, tremor is present in only about 70–90 percent of cases. Bradykinesia is often considered the most important feature of Parkinson's disease and is also present in atypical parkinsonism. It describes difficulties in motor planning , beginning, and executing, resulting in overall slowed movement with reduced amplitude which affects sequential and simultaneous tasks. Hence, it interferes with daily activities such as dressing, feeding and bathing. Facial muscles involved in bradykinesia lead to

2220-470: The exact mechanism of these symptoms remains unknown. Orthostatic hypotension is the sustained drop of blood pressure by at least 20 mmHg systolic or 10 mmHg diastolic within the first three minutes after raising to an upright position that can be seen in 30–50 percent of cases. Low blood pressure can impair the perfusion of organs situated above the heart, particularly the brain, resulting in lightheadedness . This can eventually lead to fainting and

2280-456: The exact neurobiological mechanism, and therefore possible connections with other symptoms, remains unknown. Transformation of the sensory nervous system can lead to changes in sensation that include an impaired sense of smell , disturbed vision , pain, and paresthesia . Problems with visuospatial function may arise and lead to difficulties in facial recognition and perception of the orientation of drawn lines. Peripheral neuropathy

2340-409: The first three years after disease onset, PI may indicate atypical parkinsonism. Together with bradykinesia and rigidity, it is responsible for the typical gait characterized by short shuffling steps and forward-flexed posture . Other common motor signs include a slurred and quiet voice, and handwriting that progressively becomes smaller . This latter may occur prior to other typical symptoms, but

2400-431: The gene for catechol- O -methyltransferase results in a valine to methionine mutation at position 158 (ValMet) rs4680 . In vitro, the homozygous Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart. However, in vivo the Met variant is overexpressed in the brain, resulting in a 40% decrease (rather than 75% decrease) in functional enzyme activity. The lower rates of catabolism for

2460-408: The general population. Apathy is characterized by emotional indifference and arises in about 46 percent of cases. Diagnosis is difficult, as it may become indistinct from symptoms of depression. Anxiety disorders develop in around 43 percent of cases. The most common are panic disorder , generalized anxiety disorder , and social anxiety disorder . Anxiety is known to cause deterioration in

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2520-526: The initial motor symptoms. Individual presentation of symptoms vary, although most of people affected by PD show an altered circadian rhythm at some point of disease progression. PD is associated with a variety of skin disorders that include melanoma , seborrheic dermatitis , bullous pemphigoid , and rosacea . Seborrheic dermatitis is recognized as a premotor feature that indicates dysautonomia and demonstrates that PD can be detected not only by changes of nervous tissue , but tissue abnormalities outside

2580-468: The membrane, acting extracellularly on synaptic and extrasynaptic dopamine. Soluble COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally. Despite its importance in neurons, COMT is actually primarily expressed in the liver. The COMT protein is coded by the gene COMT . The gene is associated with allelic variants. The best-studied

2640-465: The most common NPS and occurs in nearly half of all patients. It features low mood and lack of pleasure and is more prevalent in women. The diagnosis can be challenging since some symptoms of depression such as psychomotor retardation , memory problems, or altered appetite, share similarities with psychiatric signs caused by PD. It may result in suicidal ideation which is more prevalent in PD. Nonetheless, suicidal attempts themselves are lower than in

2700-682: The motor cortex. The hyperdirect pathway is an additional glutamatergic pathway that projects from the frontal lobe to subthalamic nucleus, modulating basal ganglia activity with rapid excitatory input. The striatum and other basal ganglia structures contain D1 and D2 receptor neurons that modulate the previously described pathways. Consequently, dopaminergic dysfunction in these systems can disrupt their respective components— motor , oculomotor , associative , limbic , and orbitofrontal circuits (each named for its primary projection area)—leading to symptoms related to movement, attention, and learning in

2760-528: The nervous system as well. As of 2024, the underlying cause of PD is unknown, yet is assumed to be influenced primarily by an interaction of genetic and environmental factors. Nonetheless, the most significant risk factor is age with a prevalence of 1 percent in those aged over 65 and approximately 4.3 percent in age over 85. Genetic components comprise SNCA , LRRK2 , and PARK2 among others, while environmental risks include exposure to pesticides or heavy metals . Timing of exposure factor may influence

2820-425: The number of Met alleles. Also, the effect of different genotype was greater for events that were felt as more pleasant. The effect size of genotypic moderation was quite large: Subjects with the Val/Val genotype generated almost similar amounts of subjective well-being from a 'very pleasant event' as Met/Met subjects did from a 'bit pleasant event'. Genetic variation with functional impact on cortical dopamine tone has

2880-434: The onset of PD. Risk is increased by co-exposure to, for example, glyphosate and MPTP . Harmful heavy metals include mainly manganese , iron , lead , mercury , aluminium , and cadmium . On the other hand, magnesium shows neuroprotective features. Other chemical compounds include trichloroethylene and MPTP . Traumatic brain injury is also strongly implicated as a risk factor. Additionally, although

2940-465: The presynaptic dopamine transporter (DAT), such as the prefrontal cortex (In the PFC, dopamine is also removed by presynaptic norepinephrine transporters (NET) and degraded by monoamine oxidase .). Controversy exists about the predominance and orientation of membrane bound COMT in the CNS, that is, whether this COMT process is active intracellularly in postsynaptic neurons and glia, or oriented outward on

3000-437: The progression or severity of certain stages. However, caffeine and nicotine exhibit neuroprotective features, hence lowering the risk of PD. About 85 percent of cases occur sporadic , meaning that there is no family history. PD, in a narrow sense, can be seen as a genetic disease; heritability is estimated to lie between 22 and 40 percent, across different ethnicities. Around 15 percent of diagnosed individuals have

3060-445: The regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957. Catechol- O -methyltransferase is involved in the inactivation of the catecholamine neurotransmitters ( dopamine , epinephrine , and norepinephrine ). The enzyme introduces

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3120-400: The risk for admission to a nursing home . Some of them, such as depression and anxiety, are known to precede characteristic motor signs by up to several years and may herald the development of PD, while most of them worsen as the disease progresses. Research indicates that patients with more severe motor symptoms are at higher risk for any NPS. Conversely, NPS can worsen PD. Depression is

3180-401: The same EC number. By contrast, UniProt identifiers uniquely specify a protein by its amino acid sequence. Every enzyme code consists of the letters "EC" followed by four numbers separated by periods. Those numbers represent a progressively finer classification of the enzyme. Preliminary EC numbers exist and have an 'n' as part of the fourth (serial) digit (e.g. EC 3.5.1.n3). For example,

3240-767: The substantia nigra initially presents as movement abnormalities, leading to Parkinson's further categorization as a movement disorder . In 30% of cases, disease progression leads to the cognitive decline known as Parkinson's disease dementia (PDD). Alongside dementia with Lewy bodies , PDD is one of the two subtypes of Lewy body dementia . The four cardinal motor symptoms of Parkinson's— bradykinesia (slowed movements), postural instability , rigidity , and tremor —are called parkinsonism . These four symptoms are not exclusive to Parkinson's and can occur in many other conditions, including HIV infection and recreational drug use . Neurodegenerative diseases that feature parkinsonism but have distinct differences are grouped under

3300-495: The symptoms of PD. Parkinson's disease psychosis (PDP) is present in around 20 percent of cases and comprises hallucinations , illusions and delusions . It is associated with dopaminergic drugs used to treat the motor symptoms, higher morbidity, mortality, a decrease in health-promoting behaviors, and longer nursing home stays. Additionally, it correlates with depression and may herald onset of dementia in advanced stages. Unlike other psychotic forms, PDP typically presents with

3360-578: The treatment of Parkinson's disease . Risk of liver toxicity and related digestive disorders restricts the use of tolcapone. Enzyme Commission number EC numbers do not specify enzymes but enzyme-catalyzed reactions. If different enzymes (for instance from different organisms) catalyze the same reaction, then they receive the same EC number. Furthermore, through convergent evolution , completely different protein folds can catalyze an identical reaction (these are sometimes called non-homologous isofunctional enzymes ) and therefore would be assigned

3420-453: The umbrella of Parkinson-plus syndromes or, alternatively, atypical parkinsonian disorders. Parkinson's disease can result from genetic factors or be idiopathic , in which there is no clearly identifiable cause. The latter, also called sporadic Parkinson's, makes up some 85–90% of cases. The defining symptoms affect the motor system and include tremor , bradykinesia , rigidity , and postural instability . Other symptoms may affect

3480-509: The underlying cause is unknown, melanoma is documented to be associated with PD. Low levels of urate in the blood are associated with an increased risk while Helicobacter pylori infection can prevent the absorption of some drugs, including L-DOPA . Main pathological feature is cell death of dopamine -releasing neurons within, among other regions, the basal ganglia , more precisely pars compacta of substantia nigra and partially striatum , thus impeding nigrostriatal pathway of

3540-710: The use of dopamine agonists. Cognitive disturbances can occur in early stages or before diagnosis, and increase in prevalence and severity with duration of the disease. Ranging from mild cognitive impairment to severe Parkinson's disease dementia , they feature executive dysfunction , slowed cognitive processing speed , and disrupted perception and estimation of time. Sleep disorders are common in PD and affect about two thirds of all patients. They comprise insomnia , excessive daytime sleepiness (EDS), restless legs syndrome (RLS), REM sleep behavior disorder (RBD), and sleep-disordered breathing (SDB), many of which can be worsened by medication. RBD may begin years prior to

3600-756: Was found to be associated with depressed factor of Positive and Negative Syndrome Scale (PANSS) and efficiency of emotion in schizophrenia subjects. It is increasingly recognised that allelic variation at the COMT gene are also relevant for emotional processing, as they seem to influence the interaction between prefrontal and limbic regions. Research conducted at the Section of Neurobiology of Psychosis , Institute of Psychiatry, King's College London has demonstrated an effect of COMT both in patients with bipolar disorder and in their relatives, but these findings have not been replicated so far. The COMT ValMet polymorphism also has

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