|Year : 2021 | Volume
| Issue : 1 | Page : 4-11
Role of serotonin transporter-linked polymorphic region in suicide: Beyond association, meta-analysis, and future prospects
Department of Zoology, School of Life Sciences, Sikkim University, Gangtok, Sikkim, India
|Date of Submission||16-Dec-2020|
|Date of Decision||14-Jan-2021|
|Date of Acceptance||16-Jan-2021|
|Date of Web Publication||15-Apr-2021|
Dr. Bisu Singh
Department of Zoology, School of Life Sciences, Sikkim University, Gangtok-737 101, Sikkim
Source of Support: None, Conflict of Interest: None
Serotonin transporter-linked polymorphic regions (5-HTTLPR) have been investigated intensively in suicide with inconsistent findings. However, a recent meta-analysis has observed an association of S allele with violent attempted suicide. The S allele causes a lower expression of 5-HTTLPR and is correlated with higher amygdala response to unpleasant stimuli. However, studies show that effect 5-HTTLPR genotype on mRNA expression is additive and linear. It suggests that apart from genotype, the expression of 5-HTTLPR is also controlled by epigenetic factors. Therefore, the purpose of this narrative review is to re-evaluate the findings of retrospective studies 5-HTTLPR in suicide with their limitations and highlight a new approach to understand the role of 5-HTTLPR in suicide. Reviews, meta-analysis, research articles, brief reports, and scientific correspondence were searched through PubMed, library web portal of Sikkim University, Bio-Med, and Science Direct using the terms such as “serotonin or serotonin system and suicide,” “5-HTTLPR and suicide,” “5-HTTLPR and attempted suicide,” “5-HTTLPR and completed suicide,” “5-HTTLPR meta-analysis and suicide,” and “5-HTTLPR and epigenetics.” The articles written in English were initially screened by title and later selected by abstract for possible inclusion. After the literature review, it was observed that previous studies were limited by variability of sample size, heterogeneous populations, varied social stressors, and variations in the assay and statistical methods. Hence, the cumulative study of environmental factors, 5-HTTLPR gene polymorphism, and epigenetic factors is hereby proposed in the well-defined ethnic population to understand the role of 5-HTTLPR in suicide.
Keywords: Serotonin transporter-linked polymorphic region, polymorphism, serotonin, serotonin transporter, suicide
|How to cite this article:|
Singh B. Role of serotonin transporter-linked polymorphic region in suicide: Beyond association, meta-analysis, and future prospects. Ann Indian Psychiatry 2021;5:4-11
|How to cite this URL:|
Singh B. Role of serotonin transporter-linked polymorphic region in suicide: Beyond association, meta-analysis, and future prospects. Ann Indian Psychiatry [serial online] 2021 [cited 2021 Aug 3];5:4-11. Available from: https://www.anip.co.in/text.asp?2021/5/1/4/313753
| Introduction|| |
Suicide can be defined as a behavior possessed by oneself for taking their own life deliberately or intentionally. Throughout the world, approximately 3.5% of people attempt suicide and about 2% of death comes through suicide. Familial, adoption, and twin studies are suggestive of the involvement of genetic component in the etiopathology of suicide with the complex interaction between many genes and stressful environmental conditions., Further, it has been suggested that the genetic factors may have an additive effect on environmental stressors which makes an individual incompetent to cope with psychosocial stressors. However, despite untiring research, the specific gene (s) responsible for suicide has not been identified to date. One of the common approaches to investigate and identify the candidate gene(s) for suicide has come from neurobiological studies. Thus, most of the investigations to identify the candidate genes for suicide have focused on genes involved in neurotransmission such as dopamine, serotonin, gama aminobutyric acid (GABA), and glutamate. Lately, genetic studies have indicated a link between the serotonergic system and suicidal behavior owing to its established role in sleep, mood, motor activity, behavior, emotions, neuroendocrine, neurodevelopment, and brain functions. Owing to its important role in serotonin mobilization from the synaptic cleft, many of the research groups have focused on the promoter region of serotonin transporter gene called serotonin transporter-linked polymorphic region (5-HTTLPR) to throw light in the genetic underpinnings of suicide. However, to date, the findings on the role of 5-HTTLPR in suicide have not reached a common agreement. Besides, the meta-analytic approach to investigate the role of 5-HTTLPR are largely inconsistent and the direct relationship of 5-HTTLPR with suicide could not be established. Therefore, the purpose of this review is to outline the recent findings of 5-HTTLPR in suicide and critically evaluate the results of the retrospective studies with their limitations. A new approach of study based on epigenetic changes and future challenges has been discussed.
| Materials and Methods|| |
The literature was searched through a database such as PubMed, the local library web portal of Sikkim University, Bio-Med, and Science Direct. The search was performed from December 2018 to October 2020 using the terms such as “serotonin or serotonin system and suicide,” “5-HTTLPR and suicide,” “5-HTTLPR and attempted suicide,” “5-HTTLPR and completed suicide” “5-HTTLPR meta-analysis and suicide,” and “5-HTTLPR and epigenetics.” Various published narrative reviews, meta-analysis, full-length articles, brief reports, and scientific correspondence were searched thoroughly for its relevance for review. The literature was screened by title initially, and later, they were selected by abstract for possible inclusion. Only those studies involving 5-HTTLPR and suicide were selected for the review. Research articles involving only other psychiatric disorders such as depression, schizophrenia, and bipolar disorder without the consideration of completed or attempted suicide were excluded. Further, the articles other than in English and unrelated abstracts were excluded. After the screening, thirty full-text articles published in peer-reviewed journals were selected for review [Figure 1].
Serotonin transporter-linked polymorphic region polymorphism
Being a regulator of the serotonin system, 5-HTTLPR has become a focal point of research in suicide for the last two decades. The two functional polymorphisms of 5-HTTLPR were identified in humans which were found to arise by a 44-base pair insertion or deletion in the 50 flanking regulatory regions of 5-HTTLPR leading to “long” (L) and “short” (S) variants. The presence of long and short variants of alleles leads to variation in the gene expression which is greater for L allele than the S allele. Another newly discovered polymorphism in the region of L allele is the substitution of A/G single-nucleotide polymorphism (rs25531) which can generate the two variants LA and LG. The LA variant causes its higher expression while LG variant is functionally comparable to S allele. Thus, numerous investigations have been carried out to understand the role of functional variants of serotonin transporter promoter gene polymorphism in suicide. [Table 1] summarizes the finding of 5-HTTLPR study in suicide.
|Table 1: 5-serotonin transporter-linked polymorphic regions studies in suicide|
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Psychiatric conditions, serotonin transporter-linked polymorphic region polymorphism, and suicide
One of the most intensively studied psychiatric illnesses for its association with 5-HTTLPR is depression since it accounts for approximately 15%–20% death by suicide. It is hypothesized that the interaction of 5-HTTLPR genotype with the experience of stressful life events leads to depression during adulthood. Until date, the role of 5-HTTLPR in suicide among the population of depressed individuals has not reached consensus with some reporting higher incidence of L allele with double the frequency of L/L genotype than that of controls, while others reporting a higher incidence of SS or LS genotype, whereas neutral findings were reported in some of the other studies. However, among the bipolar disorder patients, some studies reported the association of S allele with the violent suicide attempt whereas others observed the higher incidence of L/L genotype among the attempted suicide cases with a major depressive episode. Moreover, in the same study, it was observed that low-expressing genotype (S) had a significant relationship between stress, depression, and suicide but not the L/L genotype. However, other studies reported the association of SS genotype with bipolar disorder but not with the suicidal attempt. On the other hand, even though schizophrenia accounts for 5% the suicide risk, the studies conducted among the schizophrenia patients revealed no association between biallelic polymorphism of 5-HTTLPR and suicidal behavior. It has been proposed that suicidal behavior in patients with schizophrenia is instigated by the depressive mood and insight into illness but not due to psychotic symptoms. The lack of consistency in findings for the association of a particular polymorphism of 5-HTTLPR with suicide among the patients with various psychiatric conditions may be due to disease phenotype which may have varied etiological background. However, meta-analysis has shown the association of S allele with suicidal behavior in psychiatric patients. Cumulatively, it can be mentioned that the genotype provides vulnerability to the individual for adverse life events leading to depression, which is an important risk factor for suicide regardless of any psychiatric disorder.
Serotonin transporter-linked polymorphic region polymorphism, impulsive aggression, and suicide
Since serotonin is associated with modulation of anger and aggression, it was assumed to be of crucial importance in violent suicide. However, regarding 5-HTTLPR, some studies have observed an association of S allele with violent suicide, irrespective of the psychiatric disorder, whereas no association was observed for the nonviolent suicide. In concordance with the findings of nonviolent suicide, another study from the USA also did not observe the association between the promoter genotype with suicide or pathological aggression. However, meta-analysis has shown the association of S allele with violent suicidal behavior. A recent study observed that childhood trauma and 5-HTTLPR-SS genotype are independently involved in suicide attempts. It is worth mentioning here that in most of the earlier studies, the variation in the frequency of S allele was not statistically significant between suicide and controls, which is suggestive of the fact that the S allele may not be directly associated with suicidal behavior rather it is the specific trait of the suicidal act such as violent or nonviolent, lethal or nonlethal which may correlate with S allele. Moreover, studies have reported the reduction in serotonin binding in the orbital or ventral prefrontal cortex in individuals who have completed suicide. This suggests that genetic inheritance and reduction in the serotonin turnover may be involved in the severe form of suicidal behavior. Studies have found that the specific region of the brain involved in modulation of aggressive behavior is the amygdala and prefrontal cortex, and serotonin expedites the prefrontal cortex inhibition. Thus, disruption in the serotonergic system may activate the prefrontal cortex triggering the pathological aggression. Therefore, the presence of S allele may trigger lower turnover of serotonin leading to prefrontal cortex activation, which in turn may trigger pathological aggression and violent suicide.
Serotonin transporter-linked polymorphic region and suicide: Gene–environment interaction and its effects
Studies have shown that in addition to genetic factors, the environmental factors such as stress and child abuse are an important risk factor for suicide. Regarding the gene–environment effect, there is ample evidence to show that those having low-expressing genotypes are more likely to attempt suicide if they have experienced child abuse. Moreover, suicidal ideation was found to be more common among older individuals who have SS genotype and had stressful life events and social support deficit. However, unlike the widely recognized “reactivity” with the short alleles of 5-HTTLPR, some of the studies have reported the association of LL genotype with child abuse history and suicide attempt among the depressed psychiatric patients. In a recent study, it was observed that L-carriers are three times more likely to reattempt suicide as compared to SS carriers. 
It was suggested that the inheritance of specific polymorphism of 5-HTTLPR may make individuals vulnerable to stress due to the inability to disengage attention from emotion relative to neutral information which may lead to depression. Studies suggest that among the individual with SS genotype, the childhood abuse has a circuitous effect on negative urgency through brooding. It was observed that S allele carriers have a higher sensitivity to the effects of stress which increases their risk for depression and suicidality. Moreover, the children homozygous for S alleles have a greater self-referent encoding of negative stimuli than the one who possesses L alleles. Thus, the genetic makeup of an individual modulates the response of an individual to a socio-environmental stimulus. In addition to coping up with stress, 5-HTTLPR has been observed to determine the personality traits. Regarding gene–environment interaction, it is proposed that genotype does not affect at minor stress levels, whereas the short-allele carriers have more prominent reactions at moderate stress level. However, long-allele carriers may become more reactive when the stress becomes so severe that people undergo depression and need psychiatric treatment. It has been observed that in the presence of supportive parents, adolescents with SS genotype have more positive affectivity than the one who has unsupportive parents, and among the adolescents, with long allele, the role of the parents has a moderate effect. Thus, S alleles interact with both negative and positive environmental stimuli conferring its broader implications on psychological functioning. Based on the abovementioned findings, the traditional concept of the deficit-oriented connotation of the 5-HTTLPR variants should be re-evaluated. Thus, the environmental factors along with the particular variant of the genotype will dictate whether the response to the a specific stimulus would be negative or positive. Cumulatively, it can be mentioned that the interaction of genotype of an individual with the psychosocial factors is an important conferring factor for suicide.
Serotonin transporter-linked polymorphic region polymorphism and brain functions
Till date, the mechanism of association of 5-HTTLPR with brain functions and suicide is not clearly understood. A recent study observed a link between S allele carriers and susceptibility to stress in bipolar depressed patients which are mediated by corticolimbic functional connectivity. However, it is evident from the functional magnetic resonance imaging studies that individuals who possess S allele of 5-HTTLPR have higher amygdala response to unpleasant stimuli which indicate the exaggerated stress sensitivity of these individuals. More specifically, it is the left amygdala which shows an increase activation in S allele carrier. Even though the effect of a genotype on amygdala function is not clearly understood, in vivo experiments have revealed a negative correlation between left amygdala function and serotonin transporter levels. Experiments have also observed an association' of S allele with low serotonin transporter availability in the brain of suicide attempters. This suggests that low-expressing genotype of 5-HTTLPR may trigger the suicidal tendency by lowering the availability of serotonin transporter in the brain, thereby increasing the activation of the left amygdala to unpleasant stimuli. Studies have also suggested that serotonin transporter is of utmost importance in the responsiveness of the left amygdala during emotional processing. However, positron emission tomography (PET) and single-photon emission computed tomography (SPET) studies are not consistent on the role 5-HTTLPR polymorphism on serotonin availability in the brain. Some of studies reported increased availability of serotonin transporter in the midbrain, putamen, and caudate among the homozygous LALA genotype individuals, whereas others reported SS homozygous genotype individuals to have an increased serotonin transporter levels. Contrastingly, other studies with SPET and PET revealed no significant association between the 5-HTTLPR polymorphism and serotonin transporter availability in the brain. The explanation put forward for the findings is that 5-HTTLPR polymorphism has a direct effect on neurodevelopment, and the way brain functions in adulthood are attributed to the earlier neurodevelopmental changes. Further, it has been proposed that 5-HTTLPR polymorphism may have a modulatory effect on the formation of serotonin circuitry in early developmental stages which may be more or less fixed during adulthood. Therefore, the availability of serotonin to the adult brain is perhaps under the control of some other homeostatic mechanisms independent of 5-HTTLPR. To support of this view, studies have observed that serotonin transporter levels are not solely dictated by genes but by numerous other factors, such as daylight, stress, sex, and age. The additional support for the neurodevelopmental viewpoint came from the findings that the short-allele carriers have a reduced gray matter in anterior cingulate and amygdala as well as reduced connectivity in these regions. Moreover, studies on serotonin knockout mice were found to have morphological alterations in the basolateral amygdala. Besides, it has been reported that apart from an increased amygdala response to emotional stimuli, the S allele carriers were also found to have reduced amygdala volume.
In conclusion, it can be mentioned that 5-HTTLPR polymorphism may affect the availability of serotonin transporter in the developing brain. The unavailability of the serotonin transporter may have a detrimental effect on early neurodevelopment and structural integrity of the brain which in turn may confer vulnerability to stress and manifest the suicidal behavior.
Serotonin transporter-linked polymorphic region study in suicide: Research gaps
The inconsistencies so far observed in the 5-HTTLPR research concerning suicide may be attributed to several factors. One of the reasons for the none agreement of the findings may be consideration of the types of suicide such as violent versus nonviolent, varied psychiatric conditions, variability of sample size, heterogeneous populations, varied social stressors, and variations in assay and statistical methods used.
It has been observed that being a polymorphic region, 5-HTTLPR have ethnic discrepancies in the distribution of S and L alleles among various populations.,, A meta-analysis of study from 35 countries revealed a negative correlation between the frequency of S allele and suicide rates for Caucasian ethnicity, whereas a positive correlation was observed for non-Caucasian countries. Thus, the findings of 5-HTTLPR in suicide may have largely been influenced by the ethnicity of the studied population. Therefore, one should be cautious while generalizing the findings of 5-HTTLPR across the various population. The ethnic differences in the distribution of 5-HTTLPR allele may also confer vulnerability to a population for mental disorders and thus to suicidal behavior. In our previous investigation, we have observed ethnic clustering of the suicidal phenomenon which hints toward the genetic vulnerability of certain communities for suicide. Therefore, to better understand the role of 5-HTTLPR in suicidal behavior, there is an urgent need to consider the ethnicity of the studied population, and the study should be performed in a larger sample population with sufficient power to reduce the bias of the existing results.
Meta-analysis studies and its limitations
Till date, seven meta-analysis studies have been performed to investigate the role of 5-HTTLPR in suicide. However, the only two studies have found a direct association of 5-HTTLPR with suicide while others found the association of S allele with only attempted suicide but not with the completed suicide. In another meta-analysis, the association of 5-HTTLPR L/S was observed with suicidal behavior. Nevertheless, S allele was found to be associated with psychiatric patients with violent suicide. Contrastingly, in another study, L allele was found to be associated with suicide among patients with psychiatric disorders such as bipolar disorder, major depression, and schizophrenia. However, a recent meta-analysis found the association of low-expressing alleles (S and LG) with a violent suicide attempt. One of the most important tasks in the meta-analysis is to enumerate the number of studies required to achieve P = 0.05 so that the file-drawer bias could be reduced. Even though meta-analysis is a powerful tool to increase the sample size by pooling the data of the previous studies to come to the concrete conclusion, it has a certain limitation. The meta-analysis is most likely to include only the positive results due to publication bias. Therefore, considering the negative results (which may not have been published) to the meta-analysis may give a better spectrum to the overall influence of 5-HTTLPR in suicide, and the data for it can be collected by directly communicating with the research groups. Another important issue with the meta-analysis of 5-HTTLPR with suicide is the inclusion of varied sample size heterogeneous studies. Thus, within such studies, large sample-sized individual studies have more influence on the overall results. Population stratification often affects meta-analytic studies. Thus, the variability among the individual studies such as ethnicity of the individuals included, study design, and prodromal phase for suicide may influence the results. Therefore, the heterogeneity among the individual study design will lead to ambiguity in the meta-analysis. Among the seven meta-analyses that have been carried out so far to understand the role of 5-HTTLPR in suicide, the sample size of the population varied considerably between the studies which may be attributed for the lack of consistency in the findings. Moreover, one of the important limitations of earlier studies was the lack of sufficient statistical power in individual studies to study small gene effects. Besides, most of the individual studies lack the information about individual patients as the patient characteristics can vary with respect to diagnosis, comorbidities, severity, etc., These differences can explain many of the discrepancies in the results. This problem can be mitigated when the data from the individual patients are available from all the studies which can be done by contacting the research groups who have already published their work.
Serotonin transporter-linked polymorphic region polymorphism and suicide: Unresolved questions
Studies on 5-HTTLPR have added tremendously to the genetic underpinnings and molecular basis of suicide however some issues still need consideration for further studies. One of the major risk factors for suicide is depression and the commonly associated S allele with it would actually cause the increase in serotonin through reduced serotonin reuptake. Conversely, one of the characteristic features of depression is the lower levels of serotonin. To answer this contrasting phenomenon, two probable justifications have been put forward. First, it has been proposed that for the high levels of serotonin, the brain tends to compensate by downregulating certain serotonin receptors early in development to limit the serotonergic transmission, despite its high levels. Second, high serotonin levels have a neurotrophic effect on developing brain and cause it to be more vulnerable to adverse life conditions, however, it may have differential effect when acting as a neurotransmitter later in life. Even though both these explanations justify the higher levels of serotonin, it does not cater the answer to the lower level of serotonin that is observed in depression. However, it is not known to date whether depression causes low levels of serotonin or else low levels of serotonin cause depression. Moreover, as per the traditional belief, having S allele is disadvantageous as it is responsible for fewer serotonin transporter on the cell membrane, thus making an individual vulnerable to stress, impulsiveness, and depression, which are major risk factors for suicide. However, it is still unclear why the administration of selective serotonin reuptake inhibitors which reduces the serotonin transporter function improves depression and impulsiveness. In addition, if the proposed downregulation of certain serotonin receptors (by having S allele) early in development is an adaptive mechanism to limit the serotonergic transmission, it is still unknown how in the heterozygous condition (S/L) the effect of L allele is suppressed. More intensive research with sophisticated modern tools and techniques may help to address these issues to better understand the role of 5-HTTLPR in suicide.
Epigenetics: The future of serotonin transporter-linked polymorphic region research in suicide
Till date, it was understood that the functional dominance of S alleles has a major impact on the availability of serotonin transporter and it was correlated with various aliments including suicide. Thus, most of the studies observed that the homozygosity of S allele is associated with lower serotonin transporter. However, it was not understood whether the S allele demonstrates a dominant effect in the heterozygous state as well. Studies addressing this issue observed that the values of mRNA obtained from S, L heterozygotes actually lie arithmetically between the values obtained from S and L homozygotes. Thus, it shows that the effect of 5-HTTLPR genotype on mRNA expression is additive and linear and not the dominant type as previously suggested. This observation points that apart from genotype, the expression of 5-HTTLPR is also controlled by other epigenetic factors. Therefore, to refine the previous study and to understand the exact role of 5-HTTLPR in suicide, the genotypic studies along with the consideration of epigenetic factors in the regulation of expression of the 5-HTTLPR gene are imperative. Till date, epigenetic changes of 5-HTTLPR in suicide has not been considered for the study. Therefore, the future approach of study including genotyping of 5-HTTLPR; consideration of epigenetic factors; and the expression of mRNA in the brain tissues, plasma, and platelet will throw more light in this respect.
Studies in the animal model have shown that epigenetic alterations in the DNA are triggered by factors such as stress. Neurobiological and genetic studies have advocated the stress–diathesis model for suicide which suggests a complex interaction between genes, stressors, and abnormal familial psychological or physiological traits' stressful environmental factors. It is well evident that the presence of S allele does not exclusively confer for suicide; thus, the altered epigenetic changes (if any) of 5-HTTLPR may explain the vulnerability of individuals for suicide. Studies have also advocated that the methylation of the SERT loci may play a role in regulating the serotonergic function. Nevertheless, the extent of methylation may be dependent on 5-HTTLPR genotype. However, the questions remain to be answered whether various comorbid, confounding factors modulate the degree of epigenetic alterations in 5-HTTLPR in vulnerable and nonvulnerable groups for suicide. Future studies designed to unravel the role of various environmental factors (e.g., stressor or psychological factors) on the epigenetic changes in the 5-HTTLPR may throw a better picture in this respect.
Serotonin transporter-linked polymorphic region polymorphism and suicide: Future challenges
One of the major problems with the previous studies of 5-HTTLPR in suicide is the heterogeneity among the studies and lack of a sufficient number of samples to demonstrate the sufficient effect size and power. Therefore, future association studies should include a sufficient number of samples with well-defined comorbid and confounding factors. In addition, a major challenge faced in this regard (at least in developing countries) is the insufficient documentation of data (such as comorbid condition and confounding factors). On the other hand, it is highly recommended that meta-analysis should include only those studies which are having considerable homogeneity and sufficient power. One of the major challenges in this regard is to get a sufficient number of samples in those societies and culture or countries where suicide is relatively low or the inaccessibility of samples due to various reasons.
Studies have observed the differential effect of major stressors on 5-HTTLPR genotype. To throw more light in this respect, the future studies should focus on the effect of specific stressors on genotype and how it modulates epigenetic changes in 5-HTTLPR, especially on the neuronal cells. However, the in vitro culture of the neuronal cell is a major challenge. Most of the expression studies of 5-HTTLPR have been performed in lymphoblast cells. However, the epigenetic changes such as the level of methylation vary at different tissues. Therefore, it is imperative to design the future studies to understand the degree of methylation in neuronal cells, most specifically human brain cells. However, the culture of the neuronal cells in vitro condition is a major challenge as the mature neuronal cell does not undergo cell division. Thus, secondary neuronal tumor lines have been employed for the purpose in some instances, but one of the major problems is that it cannot perfectly mimic the primary cell lines. As it is mentioned above, the epigenetic changes such as DNA methylation in the normal cell and the altered cell vary considerably. Hence, the use of primary culture lines for neurons is desirable, however, it comes with the various limitations such as limited availability due to lack of its immortality. The use of neural stem cells and progenitors has been used to sort out the problems, but it also shows the intermediate phenotype between embryonic stem cells and mature differentiated neural cell. Therefore, expression study of 5-HTTLPR directly on the brain neuronal cells in vitro at this moment is challenging. Future studies with the improved cell culture technique for mature neuronal cell lines from the brain (primary neuronal cell line) will add to the expression studies of 5-HTTLPR on neuronal cells, which in turn will help to understand effect of specific stressors on genotype.
| Conclusion|| |
Suicide is a complex behavioral act, and the study of 5-HTTLPR has added tremendously to its understanding. However, there is still a long way to go to completely unravel its mystery. The detailed understanding of the interaction of environmental factors, 5-HTTLPR gene, and the epigenetic phenomenon will put the light on the functional interaction of the gene in suicidality. The advent of the new knowledge will give better insight into the role of 5-HTTLPR in suicide which may improve our understanding of its etiology and help us better equip for its prevention.
The author is in receipt of fund from the Indian Council of Medical Research (ICMR) for carrying out the research activities. The author would like to thank Mr. Jiwan Gurung for technical support during manuscript preparation and Dr. Sanjeev K Sunny for assistance during the literature search.
Financial support and sponsorship
Dr. Bisu Singh is in receipt of fund from ICMR, India, for carrying out research activities.
Conflicts of interest
There are no conflicts of interest.
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