Background
Suicidal behavior is a major health problem worldwide. Suicide has been suggested to involve catecholaminergic dysfunction and to have a genetic correlate. Many significant abnormalities in catecholaminergic dysfunction have been identified in suicide attempters and completers [
1]. For example, high concentration of noradrenaline with decreased α2-adrenergic binding has been described in the prefrontal cortex of suicide victims [
2], whereas low concentration of 3-methoxy-4-hydroxyphenyglycol, a metabolite of norepinephrine, has been observed in subjects who attempted suicide [
3‐
5].
Several lines of evidence suggest that suicide has a genetic component [
6]. Attempted and completed suicide show familial behavior. Family studies have found that those patients more likely to display suicidal behavior have parents with a history of suicidal behavioral with a heritability of about 40-50% [
7‐
11]. A large number of studies in twins has also been reported. The pooled data from seven twin studies report concordance rates for suicide or suicide attempt of 23.5% in monozygotic twin pairs and 0.13% in dizygotic twins [
12‐
14]. Furthermore, the classic adoption studies demonstrate higher suicide rates in the biological parents than in adoptive parents of adoptees who died by suicide [
13,
15]. Despite the large amount of studies conducted, the specific genes that contribute to vulnerability for suicidal behavior are unknown. One candidate gene in the study of suicidal behavior is the gene encoding the enzyme catechol-o-methyl-transferase (COMT). The biological functions of COMT make it an attractive candidate gene for suicidal behavior. COMT is a major catabolic enzyme for catecholaminergic neurotransmitters in the brain.
The COMT gene is located on the long arm of chromosome 22 at 22q11; it spans 28 kb and contains six exons. A common polymorphism of the COMT gene is the val108/158met variant (rs4680). This polymorphism is due to a G to A transition at codon 158 of the membrane bound form of COMT, which corresponds to codon 108 of the soluble form of COMT, resulting in a valine (val) to methionine (met) substitution [
16,
17]. COMT is one of the enzymes that degrade catecholamines, including dopamine [
16,
17]. The low activity COMT genotype (COMTmet/met), consisting of a met/met allele pair, yields a 3-4 fold lower enzyme activity compared to the high activity genotype (COMTval/val), which has a val/val allele pair, whereas the COMTval/met genotype produces intermediate enzyme activity [
18].
To date, the polymorphism rs4680 of COMT has been associated with a number of disorders including schizophrenia [
19], bipolar disorder [
20], major depressive disorder [
21], obsessive compulsive disorder [
22], and Parkinson's disease [
23]. Several studies have investigated the association between rs4680 of COMT and suicidal behavior. Other COMT polymorphisms that have been investigated are rs362204 and 2097603 [
24]. Actually more than fourteen case-control studies have been reported, as well as one study in trios [
25]. However, the association of COMT with suicidal behavior remains controversial. In addition, two meta-analyses have been published to date [
11,
26]. To explore the possibility that some of these COMT variants have susceptibility for suicidal behavior, we conducted a case-control study in a Mexican population and then we used the combined evidence to perform a meta-analysis of all the published data.
Discussion
In this study, we explored the association of COMTval/met (rs4680) with suicidal behavior. First a case-control study was conducted. Additionally, we performed a meta-analysis to assess the evidence of association between COMTval/met and suicidal behavior.
We could not find any association between COMTmet or COMTval allele and suicidal behavioral in a Mexican population. To our knowledge, this is the first study addressing the genetic association between COMTval/met alleles and suicidal behavior in a Mexican population. Our results are in agreement with recent reports in the literature stating the no association of COMTval/met and suicidal behavior [
26,
35]. This result is not surprising considering that complex behaviors, such as suicidal behavior, are the result of a moderate number of genes that individually have small to modest effects on disease liability [
26,
43].
Available evidence suggests that the effect of this polymorphism on suicidal behavior may be related to the lethality of suicide attempts rather than to the risk for attempting suicide per se [
11,
35]. In our study we only performed an association with attempted suicide, because we wanted to establish which COMT polymorphisms were associated with suicide attempts; this could be considered as a limitation of our study. However, other study analyzing genotype differences with respect to lethality of suicide attempts or violent attempt methods reported results similar to ours [
35].
It is worth mentioning the evidence provided by other studies reporting a positive association of the COMTval allele when compared to the control group [
5,
36‐
38]. But these results are controversial, since such association was observed in presence of the COMTmet allele in patients presenting alcohol dependency or other diseases [
33]. These differences among studies might be explained by the different diagnostic entities used. Some studies evaluated patients with alcohol dependence, while others included patients with schizophrenia, or schizoaffective or mood disorders [
33]. Other limitation could be that these association studies were conducted in various populations and different criteria were used to define the phenotypes. Other relevant factor is the difference in the size of the samples. We observed that almost all studies consisted of small samples (n < 200) and some even made subdivisions within samples (gender or affective status, for example). Hence, n was very small and had a low power of association. When we detected this limitation we decided to analyze the evidence in a meta-analysis.
We tested the probability of the association of COMTmet with suicidal behavior. However, we could not find any association between these two factors. A previous meta-analysis reported a Met association with suicidal behavior [
11]; however, this association is not strong because the results of this meta-analysis were highly dependent upon the inclusion of all the studies. When five of the six studies involved were individually removed from the analysis, the relationship between COMT and suicidal behavior was no longer significant [
11]. Our results are in accordance with other recently published meta-analysis in which no association was found between Met or Val allele and suicidal behavior [
26]. This evidence supports a lack of direct modulation of COMT on suicidal behavior.
Similarly to the results presented in a previous study, the sample sizes of the studies included in the present meta-analysis are in the low range compared to genetics studies for other diseases. Therefore, future studies comprising larger samples of completed suicide are important to determine this association. We also consider that given the small number of studies available the association is not observable.
In a first approach we observed heterogeneity; however this variation was due to four specific studies. We carried out a second analysis, in which the studies that gave rise to heterogeneity were discarded. However, no association between COMTmet and suicidal behavior was encountered. Finally, with the aim of establishing whether this association depended on completed suicide or suicide attempt, we performed a last analysis which only included suicide attempters. Once again, no association was confirmed.
Our study presents some limitations. Our case-control study lacks of a specific scale investigating suicide attempt. With regard to the meta-analysis, publication bias has to be considered, since negative studies are less likely to get published. Also, an overrepresentation of the results showing an association between the polymorphism and the investigated disorder is also possible [
44]. Although the contribution covering from genetic factors to personality traits may differ between male and female subjects, we did not analyze for gender. Other limitations are inherent in many meta-analysis of association (including this one) such as their retrospective nature and the inclusion of study-level data.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
TZC and CMB conceived the study, participated in its design, and helped to draft the manuscript. TZC, JRI, and RFT helped to perform the statistical analysis and to draft the manuscript. VSM and PGS recruited participants, and helped with the integration of data and analysis. GA, LL and HN coordinated and supervised the integration of data. All authors read and approved the final manuscript.