|Year : 2016 | Volume
| Issue : 2 | Page : 59-67
The serotonin transporter gene (triallelic 5-HTTLPR polymorphism) may associate with male depression in Han Chinese population
Pei-Shen Ho1, Chih-Lun Chen2, Chuan-Chia Chang3, Hsin-An Chang3, Yi-Wei Yeh3, Chih-Sung Liang4, Che-Hung Yen5, Shin-Chang Kuo6, Chun-Yen Chen6, Chang-Chih Huang7, Chun-Long Lin8, Ru-Band Lu9, Mei-Chen Shih3, San-Yuan Huang6
1 Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
2 Department of Psychiatry, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Tainan, Taiwan, ROC
3 Department of Psychiatry, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan, ROC
4 Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC
5 Graduate Institute of Medical Sciences, National Defense Medical Center; Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
6 Department of Psychiatry, National Defense Medical Center, Tri-Service General Hospital; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC
7 Graduate Institute of Medical Sciences, National Defense Medical Center; Department of Psychiatry, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan, ROC
8 Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, ROC
9 Department of Psychiatry, Institute of Behavior Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
|Date of Submission||29-Sep-2015|
|Date of Decision||18-Nov-2015|
|Date of Acceptance||16-Feb-2016|
|Date of Web Publication||2-May-2016|
No. 325, Cheng-Kung Road, Sec. 2, Nei-Hu District, Taipei, 114 Taiwan
Source of Support: None, Conflict of Interest: None
Background: Pharmacological, neurobehavioral, and therapeutic evidence have implicated serotonin in the pathogenesis of depression. There are conflicting reports on the association of genetic variants of serotonin transporter gene (5-HTTLPR) with major depressive disorder. The 5-HTTLPR is thought to have three primary allelic variants (rs25531): LA, LG, and S. The present study examined whether major depression was associated with tri-allelic 5-HTTLPR polymorphisms in a Han Chinese population. Materials and Methods: Bi-allelic and tri-allelic 5-HTTLPR polymorphisms were assessed in 305 patients with major depressive disorder (MD) and 313 unrelated healthy control subjects. In addition, to reduce clinical heterogeneity, subtype analyses were performed for clinically important variables, including family history of major affective disorder, age at onset, and severity of MD. Results: The bi-allelic 5-HTTLPR polymorphism was not associated with MD and its clinical subgroups. However, the tri-allelic 5-HTTLPR polymorphism was associated with major depression and with specific subgroups. In particular, in male subjects, patients with a low expressing genotype (S'/S') were at higher risk for MD than those with high expressing genotypes (S'/L' and L'/L'). This positive association was only observed in the subgroups of late-onset and moderate severity MD. Conclusions: The present study suggests that the tri-allelic 5-HTTLPR polymorphism might be a risk factor for susceptibility to either MD or its clinical subtypes in the Han Chinese male population but not in the female population. However, these results should be validated in a larger patient population that includes different ethnic samples or subdiagnosis groups.
Keywords: Major depressive disorder, serotonin transporter gene, subtypes, triallelic 5-HTTLPR polymorphism
|How to cite this article:|
Ho PS, Chen CL, Chang CC, Chang HA, Yeh YW, Liang CS, Yen CH, Kuo SC, Chen CY, Huang CC, Lin CL, Lu RB, Shih MC, Huang SY. The serotonin transporter gene (triallelic 5-HTTLPR polymorphism) may associate with male depression in Han Chinese population. J Med Sci 2016;36:59-67
|How to cite this URL:|
Ho PS, Chen CL, Chang CC, Chang HA, Yeh YW, Liang CS, Yen CH, Kuo SC, Chen CY, Huang CC, Lin CL, Lu RB, Shih MC, Huang SY. The serotonin transporter gene (triallelic 5-HTTLPR polymorphism) may associate with male depression in Han Chinese population. J Med Sci [serial online] 2016 [cited 2019 Mar 23];36:59-67. Available from: http://www.jmedscindmc.com/text.asp?2016/36/2/59/181519
| Introduction|| |
Major depressive disorder (MD) is a prevalent and disabling clinical condition that reduces patients' productivity and quality of life and also increases patient mortality. Substantial evidence from pharmacological, neurobehavioral, and therapeutic investigations have implicated serotonin (5-HT) as a major contributor to the pathogenesis of depression. The initial evidence suggesting that 5-HT contributed to clinical depression came from reports of elevated cerebrospinal fluid 5-hydroxyindoleacetic acid level in patients with depression., Another study of the effect of tryptophan depletion reported a lowering of mood in normal subjects and in patients that had recovered from depression. In addition, serotonin transporter (SERT) binding sites in the brain were found to be decreased in patients with major depression., Taken together, these results suggest a decreased 5-HT concentration in depressed individuals, which is consistent with the hypothesis that serotonergic dysfunction in central nervous system is an important contributor in the pathophysiology of MD.
The SERT terminates serotonin transmission through reuptake of serotonin from the synaptic cleft. Therefore, inhibiting SERT activity enhances the action of serotonin at the synapse. SERT participation in the modulation of depressive symptomatology is demonstrated by the therapeutic benefit derived from the administration of SERT inhibitors, also referred to as selective serotonin reuptake inhibitors and tricyclic antidepressants., Since serotonergic neurotransmission can be regulated by changes in SERT expression, it seems reasonable that genetic variants of SERT may be responsible for the central serotonin system dysregulation and thus may contribute to MD and/or treatment response.
The SERT gene(5-HTT,SLC6A4) is located on chromosome 17q11.1-q12, which spans 31 kb and consists of 14 exons., A 44 base pair insertion/deletion polymorphism (5-HTTLPR) in the promoter region has been described for this gene. A possible association between 5-HTTLPR gene polymorphisms and MD has been extensively investigated due to the established variances in transporter function resulting from these polymorphisms. The short (S) allele has been associated with lower transcriptional activity and reduced serotonin uptake in lymphoblasts  and platelets, and a marked reduction in messenger RNA levels and SERT binding in the brain  as compared with the long (L) allele. Some investigators have suggested that the 5-HTTLPR short (S) allele is associated with MD.,,, However, other investigators could not replicate these results.19-21 One possible reason for the above-mentioned conditions is the presence of higher-expressing (L) alleles, which contains a different functional polymorphism. A third functional allele (tri-allelic 5-HTTLPR polymorphism, rs25531) has been described in which an A > G (LA to LG) polymorphism is present at position 6 of the first of two 22-bp imperfect repeats that define the 16-repeat L allele. Previous functional study showed that the LA allele expressed at higher level than the LG allele and that LG is equivalent in expression to the S allele. Zalsman et al. also reported that the lower-expressing alleles (i.e., LG and S) independently predicted the greater severity of depression and predicted the greater severity of MD with moderate-to-severe life events compared with the higher-expressing LA allele. Of interest, these association results may be strengthened by the use of tri-allelic 5-HTTLPR polymorphism methods.
In the present study, we investigated the possible association of tri-allelic 5-HTTLPR polymorphisms and MD by comparing the frequency of this polymorphism in both Han Chinese patients with MD and healthy controls. In addition, it has been postulated that investigation focused on more homogenous subclinical phenotypes might increase the power to detect genes possibly involved in major psychiatric disorders., Thus, in order to reduce clinical heterogeneity, this study further examined specific patient subgroups according to clinical variables including family history of major affective disorder, the age at onset of MD, and the severity of depression.
| Methods|| |
This study was conducted in the inpatient and outpatient units of Tri-Service General Hospital, a medical teaching hospital belonging to the National Defense Medical Center in Taipei, Taiwan. The Institutional Review Board approved the protocol for the Protection of Human Subjects at Tri-Service General Hospital. Written informed consent was obtained from all participants and all study procedures were fully explained to the participants. To minimize the effect of ethnic differences in gene frequencies, the study participants were recruited from the Han Chinese population in Northern Taiwan. All the participants were unrelated, born and living in Taiwan, and had biological grandparents of Han Chinese ancestry. A total of 618 individuals were recruited.
The patient group consisted of 305 patients with MD (118 males and 187 females; mean age 38.49 ± 14.10 years, range: 18–65 years) who were consecutively recruited from the psychiatric department of Tri-Service General Hospital. Each patient was initially evaluated by an attending psychiatrist and then interviewed by a well-trained psychologist using the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Lifetime (SADS-L), to reach the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The inter-rater reliability (Kappa value) of the Chinese version of SADS-L were considered good to excellent for MD (0.79), bipolar disorder (0.71), anxiety disorder (0.86), schizophrenia (0.95), alcohol abuse and alcohol dependence (1.00), and substance abuse and dependence (0.82). All patients in this study met the DSM-IV criteria for MD on the basis of interviews and a best-estimated procedure that used all available information, including clinical observations, hospital records, and family information. Individuals with a history of substance dependence, severe medical illness, organic brain disease, or any concomitant major psychiatric disorders such as schizophrenia and bipolar affective disorders were excluded from this study. Patients were further classified into more homogeneous clinical subgroups as shown in [Table 1]: Moderate versus severe MD, early versus late onset MD, and MD with or without a family history of major affective disorders. The severity of the episode was assessed with the 17-item version of Hamilton Depression Rating Scale (HAM-D). Only subjects with a minimum score of 18 on the HAM-D entered the study. Eighty-four patients had moderate MD (HAM-D scores 18–24), and the rest of the patients met the severe major depression (HAM-D scores >24). The age at onset of the first depressive episode before 18 was defined as early-onset. Age 18 or older was defined as late-onset. Family history was defined as having one or more first-degree relatives that were affected with bipolar disorder or MD. Family history was collected from interviews, hospital record, and patient information.
|Table 1: Comparison of the mean age, gender, and genotype distributions of bi-allelic and tri-allelic (rs25531) 5-HTTLPR polymorphisms between patients with MD and healthy control subjects|
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The control group included 313 healthy volunteers (201 males and 112 females; mean age 37.82 ± 12.04 years, range: 18–65 years), recruited from the community. The Chinese version of the SADS-L , was used to screen out psychiatric conditions in the control group. Control subjects and their first-degree relatives were free of past or present, major or minor psychiatric disorders, including affective disorder, schizophrenia, anxiety disorder, personality disorder, and substance use disorders.
The whole blood was drawn from a peripheral vein using vacutainer tubes containing an ethylene-diaminetetracetic acid solution. Genomic DNA was extracted from the blood leukocytes using standard methods. Bi-allelic 5-HTTLPR (both S and L alleles) and tri-allelic 5-HTTLPR (S, LA, and LG) polymorphisms in the 5-HTT gene were detected using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. The PCR primer design and the methods of PCR-RFLP were modified from Wendland et al., and the PCR-RFLP protocol was performed in a PerkinElmer 9700 thermal cycler (Boston, MA, USA). The forward primer 5'-CTCCGCTTTGGCGCCTCTTC-3' and reverse primer 5'-GATCCTGGGAGAGGTGCAGG-3' were used for the genotyping of the 5-HTT promoter polymorphism. The bi-allelic 5-HTTLPR-L allele was 490 bp long, whereas the S allele was 447 bp in PCR products. Subsequently, the PCR products of bi-allelic 5-HTTLPR were digested by HpaII restriction enzymes for 2 h at 37°C. The LA allele remained uncut (490 bp), whereas the LG allele was cut into two DNA fragments of 395 bp and 95 bp.
In our study, the low expressing S and LG alleles were designated as S' and the higher expressing LA allele was designated as L' according to the described of Zalsman et al. Therefore, for our data analyses (described below), genotypes were classified into six groupings: S/S,S/L,L/L, S'/S', S'/L'., and L'//L'.
The independent-samples t- test and Pearson's Chi-square test were employed to compare the clinical and demographical parameters between patients with major depression and normal controls. The Hardy–Weinberg equilibrium was assessed for each group. Genotype and allele frequencies were also compared between patients and controls using Pearson's Chi-square analysis. Fisher's exact test was substituted for Pearson's Chi-square test when sample sizes were smaller than expected (<5 subjects). Multiple logistic regression analysis was also applied to correct for any possible effect of the covariates of age and gender on the risk of MD. Power analysis was performed with the use of G-power. All tests were two-tailed. Throughout the study, there are 63 hypothesis testing for the differences in genotype frequencies between patients and controls. To reduce the possibility of false positive findings due to multiple comparisons, the alpha was set at a more stringent level of 0.01 instead of 0.05.
| Results|| |
There was no significant difference in mean age between patients with MD and healthy controls, with the exception of the clinical subgroup of early and late-onset. However, significant differences were found in gender between these two groups [Table 1]. Genotype distributions of bi-allelic and tri-allelic 5-HTTLPR (rs25531) polymorphisms were in Hardy–Weinberg equilibrium, both in patients with MD and in control subjects (P > 0.1). The results of the genotype distributions for these bi-allelic and tri-allelic 5-HTTLPR polymorphisms in patients and control subjects are summarized in [Table 1]. Regarding the bi-allelic 5-HTTLPR polymorphism, no statistically significant differences were evident for the genotype and allele frequencies between patients with MD and the control subjects or between different clinical subtypes of MD [Table 1],[Table 2],[Table 3]. In the analyses of tri-allelic 5-HTTLPR polymorphism, we also found no significant association between genotype frequencies and patients with MD [Table 1].
|Table 2: Genotype distributions of the bi-allelic and tri-allelic (rs25531) 5-HTTLPR polymorphisms in female patients with major depression and healthy control subjects|
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|Table 3: Genotype distributions of the bi-allelic and tri-allelic (rs25531) 5-HTTLPR polymorphisms in male patients with major depression and healthy control subjects|
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Because gender differences were found between patients with MD and control subjects, we analyzed males and females separately. Among females neither the bi-allelic 5-HTTLPR polymorphism nor the tri-allelic 5-HTTLPR polymorphisms were significantly different in the genotype or allele frequency between patients with MD and control subjects, even when they were divided into the different subgroups of MD (P > 0.1, [Table 2]). Among male subjects, the bi-allelic 5-HTTLPR genotype frequencies also showed no associations between control subjects versus total MD subjects and between the clinical subgroups [Table 3]. Regarding genotype frequencies of the tri-allelic 5-HTTLPR polymorphism in male subjects, we found that there was only a weak association between total MD versus controls (P = 0.032), between MD without family history versus controls (P = 0.039), and between moderate MD versus controls (P = 0.033) [Table 3]. However, there was a highly significant difference in the genotype distribution and in the allele frequency between patients with major depression of late-onset and control subjects (P = 0.004).
The L'/L' genotype of the tri-allelic 5-HTTLPR polymorphism was rare in our population (<5%), and the L'/L' genotype was not found in two male subgroups of a positive family history of MD and moderate MD [Table 3]. Therefore, in the multiple logistic regression analyses, we combined the S'/L' and L'/L' genotypes for data analyses, and the S'/S' genotype as a risk factor (as a reference group) for MD after correction for age and gender. We found that the S'/L' and L'/L' genotypes in the tri-allelic 5-HTTLPR polymorphism were associated with lower risk for total MD. In the clinical subtypes of MD, we also found positive associations between S'/L' and L'/L' genotypes and late-onset MD [Table 4]. Once gender is taken into account, we found a positive association between major depression and the tri-allelic 5-HTTLPR polymorphism only existed in male subjects. In the clinical subtypes of male subjects, multiple logistic regression analyses revealed associations between the tri-allelic 5-HTTLPR polymorphism and the groups of moderate degree and late-onset [Table 5].
|Table 4: Multiple logistic regression analysis of the tri-allelic 5-HTTLPR polymorphism (rs25531) for risk of major depression and its clinical subtypes|
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|Table 5: Multiple logistic regression analysis of the tri-allelic 5-HTTLPR polymorphism (rs25531) for risk of major depression, and its clinical subtypes|
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| Discussion|| |
In terms of susceptibility to major depression and/or response to antidepressant therapy, the SERT gene is a plausible candidate gene for this disorder. The present study did not find any associations between MD and the bi-allelic 5-HTTLPR polymorphism, even when patients were divided according to gender [Table 1],[Table 2],[Table 3]. However, we observed a positive association between MD and the tri-allelic 5-HTTLPR polymorphism after correction for age and gender in a Han Chinese population, especially in male subjects [Table 3] and [Table 5]. Our results are in contrast with previous reports of a significant association between MD and the bi-allelic 5-HTTLPR polymorphism.,, However, our results are also in agreement with many studies that did not find an association between MD and the bi-allelic 5-HTTLPR polymorphism.,, There are several possible reasons for these divergent results. First, several bi-allelic 5HTTLPR and tri-allelic 5-HTTLPR variants have been identified in recent years that vary according to ethnicity. In the bi-allelic 5-HTTLPR polymorphism, our control population had a lower frequency of the L/L genotype (7.3%, [Table 1]) than Caucasian populations (approximately 30–35%)., With the tri-allelic 5-HTTLPR polymorphism, the lower-expressing LG alleles accounted for 44.0% of the L alleles (n = 81 of 184) in the study and were functionally grouped with the S allele and designated as S'. The frequencies of L'/L', L'/S', and S'/S' variants of tri-allelic 5-HTTLPR polymorphism in our Han Chinese control subjects (2.9%, 27.2%, and 70.0%, respectively) were different from the frequencies for Caucasian population (26.4%, 44.8%, and 28.8%, respectively) by Zalsman et al. Consequently, ethnic variations in the frequencies of tri-allelic 5-HTTLPR polymorphism may affect the association observed. The higher S' allele frequency in healthy control subjects may also mask the effect of the S' allele on mood disorders. Second, the control groups in the various studies have not been consistently defined. In genetic association studies, the use of suitable controls is very important. Thus, we excluded substance use disorders and other major or minor mental disorders in our controls because the lack of a carefully matched control group may cause spurious positive or negative results. Third, the diagnosis of MD and MD subtypes encompasses a high degree of heterogeneity; therefore, genetic studies may provide different results based on differences in definitions and composition of subgroup populations., Investigation of the various subtypes in this disease could reduce contradictory factors of this condition and uncover an association between genes and specific subtypes.
Regarding clinical subtypes in patients with MD, we hypothesized that the tri-allelic 5-HTTLPR polymorphism might be associated with early-onset or more severe MD or MD with a family history in female subjects. This hypothesis was based on previous reports that individuals with a family history and/or early-onset may have a genetic predisposition to develop MD suggested that the lower-expressing allele was associated with genotype-environmental risk in Caucasian females with MD., However, the present study found the opposite results in that the lower-expressing allele predicted late-onset MD in male patients [Table 3] and [Table 5]. Distinct ethnic populations have different cultures, different lifestyles, and different environmental stresses. These factors may affect the development of MD in different populations and genders and may affect the association between MD and the tri-allelic 5-HTTLPR polymorphism. To our knowledge, patients with early-onset MD have more opportunities to develop manic episodes, which mean some patients might be cases of bipolar disorders with the initial depressive episode. Thus, patients with late-onset MD might be representative of the general population of patients with MD. Moreover, male patients with MD without a family history were often recruited from the late-onset MD population. As a result, we found a weak association between those patients and controls. In addition, there were only 36 male patients with moderate MD in this study, so the weak association of this population with the tri-allelic 5-HTTLPR polymorphism may be a chance effect.
Ethnic stratification may be an important issue to reset population gene frequencies. It may produce a false positive or false negative result by chance when investigating the association between an allele and a disease. However, all of our subjects were unrelated Han Chinese subjects that came from a population in the Northern part of Taiwan that is known to be genetically homogeneous.,, All of the biological grandparents of our recruited subjects were of Han Chinese ancestry. Therefore, it was unlikely that stratification produced a false-positive result in our study. Moreover, the healthy control subjects were interviewed with the Chinese version of the modified schedule of SADS-L , to rule out psychiatric disorders. Thus, it was unlikely that cases of affective disorder were included in our control group.
With the sample size of 618 participants, we had a power of 0.60 to detect a small effect, 1.00 to detect a medium effect, and 1.00 to detect a large effect on the 5HTTLPR genotype distributions. With a power of 0.80, we were able to detect an effect size of 0.125 for a significant difference in genotype distributions. Using the allele frequencies of these two polymorphisms (n = 1236), this study had a power of 0.94 to detect a small effect, 1.00 to detect a medium effect, and 1.00 to detect a large effect. With regard to the patient subgroups, the statistical power was considerably relatively lower due to the small sample sizes. In this power analyses, effect size conventions were determined according to the method of Buchner et al. as follows: Small effect size = 0.10, medium effect size = 0.30, and large effect size = 0.50 (α = 0.05).
There are several potential limitations to this study. First, our sample size was large enough to detect an effect of SERT polymorphism, but after dividing subjects into different gender groups or/and MD subgroups, the sample size of subgroups became considerably smaller. Thus, these results should be interpreted with caution and further research regarding MD subgroups may be required. Second, our study design utilized a cross-sectional approach, and the demographic data and clinical diagnosis during the time of interview may be not the same as those assessed several years later. For example, some of the cases included in the unipolar disorder category may ultimately develop manic episode and the diagnosis will be revised as bipolar disorder, especially for those with a single depressive episode  or early-onset MD., These possibilities may also lead to bias in the results, so patients across subtypes should receive follow-up in the future. Third, literature reviews revealed that certain gene-environment interactions have been associated with MD.[24[,, In this study, we investigated the bi-allelic 5-HTTLPR and tri-allelic 5-HTTLPR polymorphisms of the 5-HTT gene only. This study did not evaluate the degree of psychosocial stressors quantitatively or gene-environment interactions, but these reasons might explain our contradictory results when compared with the report on Caucasian populations. In spite of the above-mentioned limitations, our results revealed a positive association between the tri-allelic 5-HTTLPR polymorphism and MD after correction for age and gender, especially in male subjects in a Han Chinese population.
| Conclusions|| |
Our results showed no association between MD and the bi-allelic 5-HTTLPR polymorphism in a Han Chinese population after correction for age and gender. However, we did find a positive association between MD and the tri-allelic 5-HTTLPR polymorphism when correcting for these covariates, especially in male subjects. Therefore, we suggest that the S'/S' genotype of the tri-allelic 5-HTTLPR polymorphism may be a risk factors that increases the susceptibility to MD in male Han Chinese population. Continued investigations utilizing a larger patient population and different ethnic groups or subdiagnosis groups may be warranted.
The authors thank Miss. Fan-Yi Lin and Chen-Chang Huang for their assistance in the preparation of this manuscript.
Financial support and sponsorship
This work was supported by National Science Council NSC101-2325-B-016-003 (SYH), Tri-Service General Hospital TSGHC103-133, TSGH-C104-129, TSGH-C105-124 (SYH); and Medical Affairs Bureau, Ministry of National Defense, Taiwan, MAB-104-073 (SYH), DOD102-114 (SYH), 103-M077(CHY). These funding agencies played no role in the study design, collection, analysis or interpretation of data, the writing of the report, or the decision to submit the paper for publication. We would like to thank Miss Yun-Hsin Lin for her assistance in the preparing this manuscript.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]