Role of COMT in ADHD: a Systematic Meta-Analysis
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Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable childhood-onset psychiatric disorder with significant genetic contribution. Considerable evidence has implicated involvement of dopaminergic system and the prefrontal cortex (PFC) in the pathomechanism of ADHD. The catechol-O-methyltransferase (COMT) gene is of particular interest for ADHD as its crucial role in the degradation of dopamine in the PFC. We summarized the reported findings investigating associations between COMT gene and ADHD and performed a meta-analysis of previous studies to assess the overall magnitude and significance of the association.
KeywordsADHD COMT Meta-analysis
Attention-deficit/hyperactivity disorder (ADHD) is one of the most frequent childhood onset (usually before age 7) psychiatric disorders that has about a 5.6 % worldwide pooled prevalence rate . The incidence of ADHD in boys is about four to nine times higher than in girls . The core clinical features of this disorder consist of developmentally inappropriate levels of inattention, hyperactivity, and impulsivity. These characteristics disrupt the child's functional and adaptive behaviors, and give rise to marked social, academic, occupational, and family difficulties for sufferers and their relatives [2, 3, 4]. Approximately 30 ∼ 50 % of patients have persisting symptoms as adults which result in adverse sequelae in adulthood [5, 6, 7]. Many adults with ADHD show significant impairments clinically—histories of school failure, occupational problems, and traffic accidents . Furthermore, ADHD conveys a significant risk for other comorbid diseases, such as oppositional defiant disorder, conduct disorder, learning disorders, mood disorders, and anxiety disorders. In adults with ADHD, antisocial personality disorder and substance abuse also have high prevalence besides mood and anxiety disorders [8, 9, 10, 11].
ADHD is considered as one of the most heritable psychiatric disorders. Converging evidence suggests that substantial genetic factors play a role in the etiology of ADHD. For example, family studies suggest that the prevalence of ADHD is higher among the parents (two to eight times) [12, 13], first-degree relatives (three to six times) [7, 13], and second-degree relatives (1.8 times)  of ADHD individuals compared with the comparison relatives. In adoption studies, the biological relatives of hyperactive children have a higher prevalence of hyperactivity than the adoptive relatives [15, 16, 17]; the adoptive relatives are at approximate risk with ADHD compared with the relatives of control children [18, 19, 20]. Twins studies have estimated that the mean heritability of ADHD is around 70–80 %, average 76 %, with environmental risk factors accounting for nearly 20–30 % [18, 20, 21].
Molecular genetics studies aimed at identifying the etiology of ADHD suggest that ADHD is a multifactorial polygenic disorder with minor contribution from each individual susceptibility gene. Multiple neural pathways have been implicated in ADHD such as dopaminergic, adrenergic, serotonergic, cholinergic, and nervous system development pathways . Among them, the dopaminergic pathway gets most focus. These hypotheses are based primarily upon three research areas as follows: the therapeutic efficacy of stimulant medications , the behavior and biochemistry of animal models [24, 25, 26, 27], and neuropsychological and functional neuroimaging studies [28, 29].
Although genome-wide association studies of ADHD have not been successful in detecting any significant genome-wide association, they provide evidence for associations with some traditional candidate genes such as DRD2, DBH, SLC6A2, ADRA1A, ADRB2, HTR2A, TPH2, CHRNA4, SNAP25, BDNF, and COMT, and also implicate novel candidate genes like CDH13, GFOD1, and CTNNA2 [30, 31].
The prefrontal cortex (PFC) is primary in mediating executive functions (EF) [32, 33, 34, 35], which are important for goal-directed behaviors, including planning, sustained attention, response inhibition, cognitive flexibility, behavioral flexibility, working memory, and reconstitution . It is believed that the underlying deficits in EF result in the behavioral symptoms displayed in ADHD children [37, 38, 39]. The PFC is considerably sensitive to its neurochemical environment, and both hypo- and hyperdopaminergic states will impair the PFC functions . The catechol-O-methyltransferase (COMT) gene codes an enzyme catalyzing the inactivation of dopamine within the PFC , and about 60 % of the DA degradation in the PFC is performed by COMT . Due to its important role in the PFC dopamine neurotransmission, COMT is considered as an essential candidate gene for the etiology of ADHD [35, 43, 44]. A single nucleotide polymorphism (SNP, rs4680) in COMT is the most popular SNP in ADHD and occupies the top spot of hot SNP list on the ADHD gene database (http://adhd.psych.ac.cn/), a genetic database providing researchers with a central genetic resource and analysis platform for ADHD .
Structure of COMT
COMT is a single domain α/β-folded protein which consists of a central mixed seven-stranded β-sheet flanked by eight α-helices, five on one side and three on the other side . The active site of COMT is a shallow groove located in the outer surface of the enzyme  and is composed of the S-adenosyl-L-methionine-(AdoMet)-binding domain and the actual catalytic site . The catalytic site of O-methylation in COMT is made up of several amino acids which play a significant role in the binding of the substrate, water, and Mg2+ . Mg2+ ions dominate the orientation of the catechol moiety and the activated methyl group of the AdoMet depending on an octahedral coordination to two aspartic acid residues (Asp141 and Asp169), to one asparagine (Asn170), to both catechol hydroxyls, and to a water molecule . The hydrophobic “walls” formed by some important protein residues (Trp38, Trp143, and Pro174) also make a contribution to the binding of the substrates of COMT [47, 49]. They keep the planar catechol ring in the correct position in the methylation reaction and define the selectivity of COMT toward different side chains of the substrates . A lysine residue (Lys144) in COMT which is near to one of the hydroxyl groups of the substrate acts as a general catalytic base in the base-catalyzed methyl transfer reaction .
Physiology of COMT
As mentioned above, COMT exists as two distinct isoforms: S-COMT containing 221 amino acids and MB-COMT having a 50 additional amino-terminal extension to form a hydrophobic membrane-spanning region [54, 57, 58]. MB-COMT has higher substrate affinity but lower catalytic activity than S-COMT . Although both transcripts distribute throughout most human tissues, only the longer transcript was found in 16 regions of the central nervous system coding both isoforms of COMT . S-COMT is predominantly expressed in peripheral tissues, such as blood, liver, and kidney, and it is hypothesized to be involved in detoxification and metabolism of catechol compounds [53, 61, 62, 63]. MB-COMT is expressed principally in the brain and is postulated to modulate cortical dopamine flux [54, 64, 65, 66, 67, 68]. The ratio of MB- to S-COMT protein in the human brain is about 70:30 . Both isoforms of COMT appear at astrocytes, oligodendrocytes, and neurons . Especially, MB-COMT, the main actor in human brain, is localized in axons, dendrites, and postsynaptic and presynaptic structures, as well as in lipid rafts and secretory vesicles . COMT protein in the neuropil is predominantly neuronal in origin, particularly in the PFC .
The MB-COMT polypeptide is localized in intracellular structures, and S-COMT protein is distributed in the cytoplasm and nucleus [69, 71]. MB-COMT is assigned to intracellular membranes preferentially rather than to plasma membrane, especially to the rough endoplasmic reticulum (RER). Although MB-COMT contacts closely with RER membrane, it plays its role in the cytoplasm because it resides in the cytoplasmic side of RER .
COMT has been considered especially relevant in regulating synaptic dopamine concentrations in the PFC. Because the dopamine transporters, which are efficacious in termination of synaptic action of dopamine by neuronal uptaking in the striatum, are relatively absent in the PFC. Inactivation of dopamine in the PFC appears to rely on COMT which is at significantly high levels in this region [64, 72, 73, 74, 75, 76].
The Mechanism of O-Methylation Catalyzed by COMT
As MB-COMT has a higher affinity for catechol than S-COMT, the catechol substrates located in the vicinity of the RER are preferentially methylated by RER-associated MB-COMT [59, 77]. Now that COMT resides within the cells, the inactivation of neurotransmitters catalyzed by COMT at most DA synapses takes place at the postsynaptic neuron instead of the synaptic cleft . Thus, dopamine in synaptic cleft is needed to be transported into the neuron. As the high affinity dopamine transporters are expressed at very low levels in prefrontal neurons, the transportation of dopamine is accomplished by organic cation transporters (OCTs) . The OCTs are expressed in neurons in human and rat brain, including cerebral cortex, and are able to transport dopamine [77, 79, 80].
Since the binding pocket of the methionine portion of AdoMet is in a narrow groove, deeper within the COMT molecule than the Mg2+ site and the catechol substrate site, AdoMet is the first substrate to bind to COMT during the methyl transfer reaction . Then Mg2+ follows. The binding of Mg2+ makes the ionization of the hydroxyl groups of catechol substrate easier. Finally, the catechol substrate binds to COMT . The methyl transfer goes on by a direct nucleophilic attack which happens between one of the hydroxyl groups of the catechol substrate and the methyl carbon of AdoMet in a tight SN2-like transition state [81, 82, 83]. Lys144, the catalytic base, can activate one of the catechol hydroxyls before the nucleophilic attack of the methyl group of the AdoMet . The proton from that hydroxyl is transferred to Lys144. Subsequently, the methyl group from the AdoMet is transferred to the hydroxyl group .
COMT is capable of methylating only one of the two catechol hydroxyls, and both COMT isoforms favor 3-O-methylation over 4-O-methylation .
A Variant of COMT with Different Enzyme Activity
There are several genetic variations in the coding sequences and/or regulatory regions of COMT gene that may influence the gene expression and enzyme activity. Most studies have paid attention to the effect of the Val/Met polymorphism (rs4680).
The Val/Met variant is a non-synonymous SNP consisting of a mutation from guanine to adenine in exon 4 [59, 85]. It leads to an amino acid substitution from valine to methionine at the 108th or 158th coden of S-COMT or MB-COMT, respectively [59, 85]. This change results in the observed polymorphic differences in enzyme activity and thermal stability . Analysis of the crystal structure of COMT indicates that the amino acid of this SNP site is localized on the surface of the protein [47, 86]. Compared to the Val-variant which is coded by the G-allele, the Met variant can translate an enzyme with a lower activity as well as a lower thermostability in physiologic temperature [59, 85]. These two variants show codominance. The enzyme activity of COMT presents a trimodal distribution of low (COMTLL), intermediate (COMTLH), and high (COMTHH) activities [48, 87]. The enzyme activity is reduced by three to fourfold in Met/Met homozygotes compared to Val/Val homozygotes, and Val/Met heterozygotes have an intermediate level of COMT activity and heat stability . Compared to the Val/Met and Val/Val genotypes, individuals with Met/Met genotype have the highest dopamine level and the most sustained dopamine signaling in the PFC. Accordingly, the PFC function is optimally at this level .
Neuroimaging analysis has demonstrated the influence of the Val/Met SNP on cognitive function, working memory, executive function, as well as on attention control. And the Met variant is beneficial to performance on tasks of cognitive function, working memory, executive function, and attention [88, 89, 90]. The Val allele with high activity is related to improved cognitive flexibility , while Val/Val homozygotes perform worse in working memory tasks among healthy people .
Male Sprague–Dawley rat
3-methoxytyramine (3-MT), the product of methyl transfer reaction of dopamine catalyzed by COMT, is the major metabolite of released dopamine in rat PFC.
1. Tissue dopamine levels are increased two-to three-fold in the frontal cortex of male COMT-knockout mice.
2. Male heterozygous COMT-knockout mice demonstrate increased aggressive behavior.
3. Female homozygous COMT-knockout mice exhibit increased anxiety.
Dopamine turnover is dramatically increased specifically in the frontal cortex of COMT-knockout mice without sexual difference.
1. Homozygous COMT-knockout mice result in improvement in spatial learning/working memory.
2. Heterozygous COMT- knockout mice result in impairment of recognition memory.
1. Val-tg mice manifest disrupted attentional set-shifting abilities, and impaired working and recognition memory.
2. COMT disruption improves working memory.
3. Anxiety-like behaviors are decreased in COMT-Val-tg mice and increased in homozygous COMT- knockout mice.
DA level in the PFC of COMT-knockout mice is increased by 60 %, in contrast to the striatum and nucleus accumbens.
Anxiety-related phenotypic profile is increased in female COMT-knockout mice.
The change in COMT activity influences some of the feeding behaviors of female rodentsb.
A Population Study: Meta-Analysis
To date, studies on the association between the COMT Val/Met polymorphism and ADHD reported conflicting findings. We performed a meta-analysis to combine previous data from published studies in an attempt to assess whether this polymorphism is associated with ADHD in humans substantially.
PubMed, Embase, and Google Scholar were searched for potentially relevant reports published prior to January 2013. The medical subject heading terms and/or text words used for the search were as follows: “attention deficit hyperactivity disorder” or “ADHD” or “ADD” or “attention deficit” or “hyperactivity” or “hyperkinetic syndrome” and in combination with “catechol-O-methyltransferase” or “COMT” or “methyltransferase”. Furthermore, we also used reference lists from identified articles, reviews, and meta-analyses that examined the association of COMT with ADHD to find additional literatures.
Eligible studies were selected according to the following inclusion criteria: (1) evaluating the association between Val/Met SNP of COMT gene and ADHD, (2) case–control study or haplotype-based haplotype relative risk (HHRR) procedure or transmission disequilibrium test (TDT), (3) all the participants were children (aged 4–16 years old), (4) subjects of the patient group were diagnosed as ADHD by the DSM III/IV criteria, (5) containing useful original data, and (6) published in English. Studies were excluded if (1) they did not include (or the author did not provide) sufficient data for calculation of odds ratio (OR) with the corresponding 95 % confidence interval (95 % CI) and (2) containing overlapping data and more than one study reported the same sample or its subset (to this situation, the largest dataset was included in the analysis) (Supplementary Fig. 1). When the full text or necessary data were not available, we attempted to contact the authors by emails to ask for the articles or sufficient data. Data were extracted by two independent reviewers, and the discrepancy between them was resolved by a third researcher.
Descriptive characteristics of studies include in meta-analysis
NO. of subjects
Gender Ratio (M:F)
Barr et al. (1999)
Eisenberg et al. (1999)
9.4 ± 2.5
Psychiatrist or senior psychiatrist
Hawi et al. (2000)
Tahir et al. (2000)
Two child psychiatrists
Manor et al. (2000)
10 ± 0.94
Payton et al. (2001)
9.1 ± 1.8
DSM-IV, DSM-IIIR, ICD-10
Two child psychiatrists and 1 child
Qian et al. (2003)
10.4 ± 2.6
One psychiatrist and 1 senior psychiatrist
Zhang et al. (2003)
12.4 ± 2.2
Taerk et al. (2004)
9.1 ± 1.8
Trained research personnel
Belgrove et al. (2005)
Turic et al. (2005)
9.2 ± 1.8
DSM-IV, DSM-IIIR, ICD-10
Bobb et al. (2005)
9.02 ± 2.22
Caucasian, African American, Hispanic, Asian, and other
Jiang et al. (2005)
11.3 ± 0.8
2 Child psychiatrist
Kereszturi et al. (2008)
Song et al. (2009)
9.27 ± 1.89
Elia, J et al. (2009)
10 ± 3.15
North Americans of European descent
Das et al. (2011)
7.28 ± 2.67
Ribases, M et al. (2012)
9.3 ± 2.6
We performed cumulative meta-analysis and sensitivity analysis to estimate the sources of heterogeneity. Cumulative meta-analysis demonstrated a trend of association as published data accumulated, showing that the cumulative results stabilized after 2000 (Supplementary Fig. 5). For sensitivity analysis, the pooled ORs did not change qualitatively after excluding one single study each time. It suggested that the results of this meta-analysis were stable (Supplementary Table 1). The funnel plot was substantially symmetrical, showing no evidence of publication bias (Supplementary Fig. 6). And the Egger's linear regression model (t = −0.1047, df = 16, P = 0.9179) and the Begg's rank correlation test (Kendall' tau = −0.0196, P = 0.9405) also suggested publication bias was not significant.
The Val/Met functional SNP in COMT gene has been intensively investigated in the association with physiological functions and behavioral phenotypes related to the PFC and hippocampal information processing [88, 90, 97]. Studies on the predisposition to psychiatric disorders suggest that this SNP affects a broad range of psychiatric disorders including schizophrenia [90, 98, 99], bipolar affective disorder [100, 101], unipolar affective disorder , obsessive-compulsive disorder (OCD) [103, 104, 105], and substance abuse [106, 107]. Velocardiofacial syndrome (VCFS), also known as DiGeorge syndrome and 22q11.2 deletion syndrome, is a kind of congenital disorder caused by a hemizygous microdeletion on chromosome 22q11 . The COMT gene is one of the top-priority candidate genes for susceptibility to mental disorders located in the deleted region. The deletion of one copy and low activity from the remaining allele of COMT contribute to the psychiatric symptoms in these patients. Previous studies find that the 158Val/Met COMT polymorphism is significantly associated with ADHD and OCD in VCFS individuals, and the low-activity Met allele acts as the risk allele .
Since the PFC and the dopaminergic pathway have been postulated to be involved in the pathogenesis of ADHD [110, 111, 112, 113, 114], we set focus on the contribution of the Val/Met polymorphism of COMT to the etiology of this psychiatric disorder. Albeit we failed to detect an association between the Val/Met SNP and ADHD with a meta-analysis, biochemical, pharmacological, neuroimaging, and animal studies indicate the involvement of the COMT gene in ADHD. There are a number of possible reasons for the absence of an association between the Val/Met SNP and ADHD. The clinical heterogeneity of ADHD itself (such as clinical syndrome and definition of the phenotype) and the distinct comorbid conditions (such as conduct disorder, depression, and tics) may mask a real association. Like most psychiatric disorders, the analysis of correlations between genotypes of COMT gene and behavioral phenotypes of ADHD suffers from bias because ADHD does not follow classic Mendelian patterns of inheritance. As for the clinical heterogeneity of ADHD, large numbers of samples are needed. While the sample included in our meta-analysis is obviously insufficient compared with the large samples in the genetic studies on other psychiatric diseases (the meta-analysis for schizophrenia are provided with approximately 3,500 or even more participants on average ).
The demographic variables of the analysis population which has potential for conflicting results are noteworthy. For example, ethnicity, gender, age, and so on. Among the individuals from different geographic regions and ethnic backgrounds, the distribution of the low activity Met allele varies widely from 0. 01 to 0.62, and this result in the diversity of COMT enzyme activity among different ethnic groups presumably . Gender is another important factor in neuroscience  and psychiatry . Animal and clinical studies have detected gender differences in the dopaminergic pathway. COMT-deficient mice exhibit sexually dimorphic effects on dopamine levels which are directed by the differences in hormonal environment . The COMT Met allele with low enzyme activity is preferentially transmitted to the male ADHD subjects, while the Val allele possesses a higher frequency in female ADHD probands than female controls . Global cerebral metabolism in girls is 19.6 % lower than in boys of ADHD . Some studies could only detect the association between the COMT Met allele and ADHD, OCD, and other psychiatric disorders in males [104, 121, 122]. There is a positive correlation between COMT activity and age proved by rat studies [123, 124, 125], while DAT density shows a negative correlation with age . Data in both animals [127, 128, 129] and human [125, 130, 131] represent age-related decrease in monoamine content and metabolism. The importance of inactivating dopamine by COMT within the PFC is developmentally regulated, and dopamine metabolism achieved by DAT is more important than that by COMT in young ages. It is in accordance with the previous findings that the DAT gene is associated with ADHD, while COMT is not.
ADHD is a polygenetic and multi-determinant disorder that both genes and environment factors appear to be complex and interactively involved in this disorder. Some other polymorphic sites in COMT gene, haplotypes, and additional genetic risk factors are previously implicated in the regulation of COMT function in addition to the Val/Met SNP. For example, rs2097603 is observed to further reduce the enzyme activity of 158 Met COMT in human lymphocytes as well as in the PFC, and rs165599 which is shown to be associated with schizophrenia intensively  affects the expression of COMT mRNA . There are several risk COMT haplotypes that could reduce COMT protein level and enzyme activity significantly . Several other candidate genes in dopaminergic neurotransmitter system which mainly target dopamine transport, release, and uptake are also associated with ADHD such as DRD2, DRD4, DRD5, and DAT1 [13, 135]. Moreover, distinct environmental influences such as maternal prenatal smoking or drinking, family conflict, and poor quality of parent–child relationships in the populations of the studies are implicated in the causation and outcome of ADHD [18, 20, 21]. In other words, ADHD does not stem from errors in a single variation but from additive effects of defects in more than one gene, multiple genetic interactions, and gene–environment interactions. Thus, a specific effect of a single gene may not be detected. Furthermore, the lack of association between the SNP and risk of ADHD should be confirmed by a more sophisticated analysis such as equivalence-based method analysis .
Considerable evidence above reveals that the COMT Val/Met SNP is germane to ADHD and becomes one of the most popular SNPs in ADHD. However, the negative result of the meta-analysis on involvement of the COMT Val/Met polymorphism in increasing the risk for ADHD cannot be considered definitive. In the studies afterwards, an increased number of homogeneous subjects are needed to be employed, and restrictions of study individuals' features (such as ethnicity, age, gender, and so on) could minimize sample heterogeneity to obtain overall convictive conclusions. The aspects of gene–gene and gene–environment interactions in addition to risk haplotypes of COMT gene should be paid more attention.
This work is supported by the National Nature Science Foundation of China (NSFC) (81101016).
Conflicts of interest
The authors have declared no conflicts of interest.
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