TPH2 -703G/T SNP may have important effect on susceptibility to suicidal behavior in major depression

Background

Serotonergic system-related genes can be good candidate genes for both major depressive disorder (MDD) and suicidal behavior. In this study, we aimed to investigate the association of serotonin 2A receptor gene -1438A/G SNP (HTR2A -1438A/G), tryptophan hydroxylase 2 gene -703G/T SNP (TPH2 -703G/T) and serotonin 1A receptor C-1019G (HTR1A C-1019G) with suicidal behavior.

Methods

One hundred and eighty one suicidal depressed patients and 143 non-suicidal depressed patients who met DSM-IV criteria for major depressive disorder were recruited from patients who were admitted to Korea University Ansan Hospital. One hundred seventy six normal controls were healthy volunteers who were recruited by local advertisement. Patients and normal controls were genotyped for HTR2A -1438A/G, TPH2 -703G/T and 5-HT1A C-1019G. The suicidal depressed patients were evaluated by the lethality of individual suicide attempts using Weisman and Worden's risk-rescue rating (RRR) and the Lethality Suicide Attempt Rating Scale-updated (LSARS-II). In order to assess the severity of depressive symptoms of patients, Hamilton's Depression Rating Scale (HDRS) was administered. Genotype and allele frequencies were compared between groups by χ² statistics. Association of genotype of the candidate genes with the lethality of suicidal behavior was examined with ANOVA by comparing the mean scores of LSARS and RRR according to the genotype.

Results

There were statistically significant differences in the genotype distributions and allele frequencies of TPH2 -703G/T between the suicidal depressive group and the normal control group. The homozygous allele G (G/G genotype) frequency was significantly higher in suicidal depressed patients than in controls. However, no differences in either genotype distribution or in allele frequencies of HTR2A -1438A/G and HTR1A C-1019G were observed between the suicidal depressed patients, the non-suicidal depressed patients, and the normal controls. There were no differences in the lethality of suicidal behavior in suicidal depressed patients according to the genotypes of three polymorphisms.

Conclusion

Our results suggest that TPH2 -703G/T SNP may have an important effect on susceptibility to suicidal behavior. Furthermore, an increased frequency of G allele of TPH2 SNP may be associated with elevated suicidal behavior itself rather than with the diagnosis of major depression and may increase risk of suicidality, independent of diagnosis.     

A case-control association study of serotonin 1A receptor gene and tryptophan hydroxylase 2 gene in attention deficit hyperactivity disorder

Serotonergic system-related genes are likely to be involved in mechanisms underlying attention deficit hyperactivity disorder (ADHD). We investigated the association of serotonin the 1A receptor C-1019G single nucleotide polymorphism (HTR1A C-1019G SNP) and tryptophan hydroxylase 2 gene –703G/T (TPH2 –703G/T) SNP with ADHD.     

Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression

Summary Several studies have linked 5-HT1A C1019G and BDNF G196A (Val66Met) gene polymorphisms to major depressive disorder (MDD) and the actions of antidepressants. We attempt to show that the interaction between 5-HT1A and BDNF polymorphism predicts the risk of treatment-resistant depression. The sample consists of 119 patients with treatment-resistant MDD and 392 controls. 5-HT1A C1019G and BDNF G196A (Val66Met) polymorphisms were studied. The combination of 5-HT1A GG and BDNF GA + AA genotypes is associated with an increased risk of depression.     

The C(-1019)G 5-HT1A promoter polymorphism and personality traits: no evidence for significant association in alcoholic patients

The 5HT1A receptor is one of at least 14 different receptors for serotonin which has a role in moderating several brain functions and may be involved in the aetiology of several psychiatric disorders. The C(-1019)G 5-HT1A promoter polymorphism was reported to be associated with major depression, depression-related personality traits and suicidal behavior in various samples. The G(-1019) allele carriers are prone to depressive personality traits and suicidal behavior, because serotonergic neurotransmission is reduced.     

Direct and buffering effects of social support on depressive symptoms of the elderly with home help

The purpose of the present study was to examine the prevalence of depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CES-D) and the effect of life stressors or social support on depressive symptoms in 303 elderly people receiving social services at home. We conducted a questionnaire survey six times with a 1-month interval. In the initial wave of questionnaires, 92 (31%) scored 16 points or above on the CES-D, indicative of a risk for depression. Before life stressors, subjects with low-level support showed significantly more severe depressive symptoms than those with high-level support. Subjects with low-level support were significantly more depressive after life stressors than they had been before, whereas those with middle- and high-level support showed no such difference. The former and latter results seem to suggest the direct and buffering effects of social support on depressive symptoms, respectively.     

Depressive symptomatology in coronary artery bypass graft surgery patients.

Depression is commonly reported in coronary artery bypass graft (CABG) surgery patients. This study assesses the relationship of preoperative characteristics, life stressors, social support, major cardiac and neurologic outcomes and other complications to depressive symptomatology. Demographic and clinical data, CES-D score and information on life stressors and social support were collected from 237 patients; 92% completed 6-month follow-up. CES-D score > or = 16 was defined as significant depressive symptomatology. Significant depressive symptomatology was found in 43% of patients preoperatively and 23% postoperatively. In multivariate models, low social support (p = 0.008), presence of at least one life stressor within a year of surgery (p = 0.006), moderate to severe dyspnea (p = 0.003), little to no available help (p = 0.05) and less education (p = 0.05) were associated with higher preoperative CES-D score, while longer intensive care unit (ICU) stay (p = 0.0001) and little or no available help (p = 0.0008) predicted higher postoperative CES-D scores when controlling for preoperative CES-D scores. Neither pre- nor postoperative depressive symptomatology was related to major outcomes or other complications. A high rate of significant depressive symptomatology exists in CABG patients preoperatively, and it decreases significantly postoperatively. Patients with the above preoperative characteristics as well as those who stay in the ICU postoperatively for more than 2 days might benefit from psychosocial interventions.     

Association of HTR1A gene polymorphisms with obsessive–compulsive disorder and its treatment response: the influence of sex and clinical characteristics

Objective: There have been controversial results in the literature on the association between HTR1A polymorphisms (rs10042486, C-1019G, and Gly272Asp) and obsessive–compulsive disorder (OCD). Here, the plausibility for such genetic and pharmacogenetic association was investigated by assessing a sample of Iranian OCD patients.

Method: OCD patients had fulfilled the criteria for DSM-IV-TR with Y-BOCS scores higher than 9. A total of 207 controls and 205 patients’ blood samples were genotyped by means of PCR-RFLP.

Results: The results showed that there was no association between these three SNPs and the treatment response. The distribution of rs10042486 genotypes was significantly different in the patients compared to the controls. The association analyses of the C-1019G showed significant differences in the genotypic frequency of the patients with or without a positive family history of psychiatric disorders. Similar differences in female patients were also observed. We found that the age of onset also associates with the C-1019G polymorphism but only in the female patients. No association of Gly272Asp polymorphism and OCD was observed in this study.

Conclusion: We concluded that among the HTR1A polymorphisms, only the association of rs10042486 CT genotype and OCD was statistically significant. The association of C-1019G with OCD by considering the age of onset and family history was just significant in the female patients. No significant association between the studied HTR1A SNPs with treatment response was observed. Acquiring both positive and negative pharmacogenetic outcomes in each population helps to select the appropriate medication for a particular patient with fewer side effects.     

Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression

OBJECTIVE: The association between stressful life events and the onset of major depression decreases as the number of previous depressive episodes increases. How do genetic risk factors for major depression impact on this "kindling" phenomenon? In particular, do those at high genetic risk exhibit an increase in the speed of kindling, or are they "prekindled"? METHOD: Using discrete-time survival analysis, the authors examined the interaction between genetic risk, number of previous depressive episodes, and life event exposure in the prediction of episodes of major depression in female-female twin pairs from a population-based registry. The twins were interviewed four times over a 9-year period, producing 92,521 person-months of exposure. RESULTS: The decline in the association between stressful life events and risk for major depression as the number of previous depressive episodes increased was strongest in those at low genetic risk and was weak to absent in those at high genetic risk. In the absence of previous depressive episodes, those at high genetic risk frequently experienced depressive episodes without major environmental stressors. CONCLUSIONS: Genetic risk factors for depression produce a "prekindling" effect rather than increase the speed of kindling. The "kindled" state, wherein depressive episodes occur with little provocation, may be reached by two pathways: many previous depressive episodes, perhaps driven by multiple adversities, and high genetic risk.     

Religious denomination as a symptom-formation factor of depression in older Dutch citizens

OBJECTIVES: The type of symptoms in depression is likely to be influenced by cultural environment. As religion represents an important cultural resource for older adults, it is hypothesised that religious denomination represents a symptom-formation factor of depression in the older generation. Focusing on older Dutch citizens, it is expected that depressed Calvinists report: (1) less depressed affect, (2) more vegetative symptoms, and (3) more guilt feelings, than Roman Catholics and non-church members. METHODS AND PROCEDURES: The Center for Epidemiologic Studies Depression Scale (CES-D) was used to distinguish depressed (N=395) and non-depressed (N=2333) older adults, and to assess depressive symptom-profiles. The Diagnostic Interview Schedule (DIS) was used to assess major depressive episodes and criterion-symptoms of depression. RESULTS: Depressed Calvinists, especially males, had higher scores on the vegetative CES-D subscale. The same was found for non-church members with Calvinist parents. Among those who have had a major depressive episode in later life (N=84), support was found for all hypotheses. Feelings of guilt were also more prevalent among Roman Catholics. CONCLUSIONS: Religious denomination modified the type of symptoms in late-life depression. As a Calvinist background was associated with less depressive affect and more inhibition, there is a risk of underdiagnosis of major depression in older Calvinists in The Netherlands.     

A model for predicting depression in elderly tenants of public housing

To assess the prevalence of and risk factors for depression in an older population, the Multilevel Assessment Instrument (MAI) and the Center for Epidemiological Studies Depression Scale (CES-D) were administered to 176 elderly residents of a public housing apartment building in Indianapolis. The 41 patients diagnosed by the CES-D as depressed had significantly lower scores on MAI measures of psychological adjustment, cognitive function, and physical health compared with the nondepressed respondents and were more likely to have had episodes of anxiety and depression in the year before the study. Four variables--respondents' overall physical health as measured by the MAI, days spent sick in bed during the past year, living alone, and educational level--explained some of the variance between the CES-D scores of the depressed and nondepressed patients. A model for predicting current levels of depressive symptomatology based on scores on each of these four variables distinguished the depressed from the nondepressed tenants more than 80 percent of the time.     

Prevalence and predictors of depressive symptoms in older premenopausal women: the Harvard Study of Moods and Cycles

BACKGROUND: The Harvard Study of Moods and Cycles is a community-based cohort study designed to evaluate the relationship between major depression and changes in menstrual and ovarian function. METHODS: All women aged 36 to 44 years with a verifiable address from 7 Boston, Mass, metropolitan communities were selected from the Massachusetts Town Books. A self-administered questionnaire assessed demographic characteristics and menstrual history, depression history, and current depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D]) in 4161 women. RESULTS: We observed a score of 16 or more on the CES-D in 22.4% of women surveyed, and 8.6% scored 25 or more. Widowed, divorced, or separated women were twice as likely as married women to have depression scores greater than 16 (95% confidence interval, 1.6-2.8), and smokers in the upper tertile of pack-years were 1.9 times more likely to have CES-D scores of 16 or more (95% confidence interval, 1.5-2.3). Relative to nulliparous women, those with 1 or 2 children had a 30% lower risk of historic mood disorder, and those with 3 or more children had an even greater reduction in risk (odds ratio, 0.4; 95% confidence interval, 0.3-0.6). Menstrual cycle irregularities were largely unassociated with current or past depression. However, 5 of 8 premenstrual symptoms were significantly associated with CES-D scores of 16 or more. CONCLUSIONS: These findings corroborate the prevalence of depression reported by other community-based studies, and also support a relationship between depressive symptoms and marital status, cigarette smoking, nulliparity, and premenstrual symptoms.     

Suicide,stress and serotonin receptor 1A promoter polymorphism -1019C>G in Slovenian suicide victims

Implication of serotonergic system in suicide and suicide attempts has been discussed for several years. One of the most abundant serotonin receptors in the mammalian brain is the receptor 1A (5-HT1A); studies of its polymorphisms and suicide have provided very inconsistent results so far. The suggestion that the G allele depresses HTR1A autoreceptor expression, and therefore reduces serotonergic neurotransmission that might predispose to depression and suicide, made the promoter polymorphism -1019C>G a very promising candidate gene. In our study we analyzed promoter polymorphism -1019C>G on 323 suicide victims and 190 controls (all of Slovenian origin), taking into account sex, suicide method, and in case of suicide victims also stressful life events. Differences in the distributions of genotype and allele frequencies were not statistically significant between suicide victims and control group, and the same was found for distributions according to sex and suicide method. For 62 suicide victims information about stressful life events in the month prior to the suicide and in childhood was provided. For analysis we combined CG/GG genotypes and compared them to the CC genotype. More stressful life events in the month prior to the suicide were reported for the subgroup with CC genotype (mean number of events = 2.53; SD = 1.50) in comparison to subgroup with CG/GG genotypes (mean number of events = 1.58; SD = 1.32; P < 0.05). However, subgroups of suicide victims with CC or CG/GG genotypes did not differ regarding numbers of reported stressful life events in childhood (P > 0.05). Our study provides no evidence for the implication of HTR1A promoter polymorphism in suicide in general, but it suggests further studies that would take into account the interconnected network of suicide completion, genetic background and stress, beside other risk factors.     

Effect of 5-HT1A receptor gene polymorphism on negative and depressive symptom response to antipsychotic treatment of drug-naive psychotic patients

OBJECTIVE: The serotonin 5-HT(1A) receptor may modulate some of the negative, cognitive, and affective symptoms of schizophrenia and is a potential target of action of some antipsychotic drugs. A functional polymorphism in the promoter region of the 5-HT(1A) receptor gene is associated with depression and suicidal behavior. The authors sought to determine whether this polymorphism influences symptom response to antipsychotic drug treatment. METHOD: Sixty-three drug-naive patients with first-episode psychosis who were genotyped for the -1019C/G polymorphism were recruited for this study and received standard care. The Positive and Negative Syndrome Scale and the Calgary Depression Scale were used to monitor symptom changes over 3 months. RESULTS: The polymorphism was associated with, and accounted for much of the variance in, changes in negative and depressive symptoms but not positive symptoms. CONCLUSIONS: These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.     

Serotonin 1A receptor genetic variations, suicide, and life events in the Iranian population

Aim: The association of serotonin 1A receptor (5‐HTR1A) gene polymorphisms with suicidal behavior has been reported in several previous studies, but the results have been inconsistent, which might be due to ethnic differences. The aim of the present study was therefore to investigate the association between polymorphisms ?1019C>G, 47C>T (Pro16Leu) and 815G>A (Gly272Asp) and suicidal behavior, taking into account age, gender, and the presence of stressful life and loss events in 1 year prior to suicide. Methods: A total of 191 suicide victims and 218 healthy control subjects were included in the present study. 5‐HT1RA gene polymorphisms were determined on polymerase chain reaction–restriction fragment length polymorphism. Results: The distribution of ?1019C>G genotypes was significantly different in suicide victims and healthy controls (P = 0.002), and the GG genotype was associated with a significantly higher number of more stressful life and loss events in the suicide victims (P = 0.017, P = 0.037, respectively). The distribution of 47C>T (Pro16Leu) and 815G>A (Gly272Asp) genotypes was not significantly different in the suicide victims and control subjects (P > 0.05). Moreover, these genotypes were not associated with stressful life and loss events (P > 0.05). Conclusion: The frequency of the ?1019G allele in the 5‐HTR1A gene was higher in suicide victims (with stressful life events) as compared with the control group. In contrast, neither 47C>T (Pro16Leu) nor 815G>A (Gly272Asp) polymorphisms were related with suicide and stressful life events.     

5-羟色胺1A受体基因C（-1019）G多态性与精神分裂症的关联分析

目的:探讨云南地区汉族人群中5-羟色胺1A(5-HT1A)受体基因C(-1019)G多态性与精神分裂症的关联,及其对症状组成、前额叶执行功能的可能影响. 方法:应用阳性与阴性症状量表(PANSS)、简明精神病评定量表(BPRS)、外显攻击量表(OAS)等评定患者症状,威斯康星卡片分类测验(WCST)评定精神分裂症和正常人前额叶执行功能.142例精神分裂症患者和84名正常对照分别用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法进行基因分型. 结果:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性在精神分裂症和正常人之间的各量表分差异有显著性(P=0.001).C(-1019)G多态性对PANSS中因子被动淡漠性社会退缩(N4)(P=0.010)、言语缺乏主动性和流畅性(N6)(P=0.004)、阴性症状总分(NT)(P=0.013)、紧张(G4)(P=0.005)、自发社交回避(G16)(P=0.013),以及BPRS中的因子4激活性(P=0.026)等条目得分的形成影响有显著性.C(-1019)G多态性与WCST各条目不相关. 结论:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性与精神分裂症显著相关,对精神分裂症症状组成可能起一定作用,但与WCST反映的前额叶执行功能状态并无显著相关.     

No association of the T102C polymorphism of the serotonin 2A receptor gene (HTR2A) with suicidality in schizophrenia

Additional evidence for a role of serotonin (5-HT) in the pathogenesis of suicidal behavior is provided by a recent report that the 5-HT2A (HTR2A) T102C polymorphism was associated with suicidality in patients with major depression. Three other studies have, however, failed to find an association between this polymorphism and suicidality in major depression. The goal of the present study was to test the association of allele C of T102C HTR2A polymorphism with suicidality in patients with schizophrenia or schizoaffective disorder. Seventy-one patients with DSM-III-R diagnosis of schizophrenia or schizoaffective disorder were included in the study. Patients were genotyped for the T102C HTR2A polymorphism. Information about lifetime suicidality was obtained during the course of SADS interviews. In addition, current suicidality was assessed by the Hamilton Depression Scale in 46 patients. There were no significant differences in allele frequencies and genotype distributions between suicidal and non-suicidal patients using lifetime or current suicidality measures. The results of this study did not demonstrate a robust association of the allele C of the T102C HTR2A polymorphism with lifetime or current suicidality in patients with schizophrenia. However, the mean Hamilton Depression Scale item for current suicidality was significantly higher in patient with genotype T/C compared to those with genotype C/C (p = 0.01) and marginally higher than for the patients with genotype T/T (p=0.06). The relatively small sample size suggests a study with a larger sample and greater power would be of interest.     

Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study.

BACKGROUND: Serotonin 1A receptors (5-HT(1A)) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT(1A) and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT(1A) G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT(1A) than healthy volunteers (controls). We measure 5-HT(1A) in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. METHODS: Genotyped and determined 5-HT(1A) binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. RESULTS: No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. CONCLUSIONS: AN have higher 5-HT(1A) than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT(1A) receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT(1A).     

The serotonin transporter polymorphism (5‐HTTLPR): allelic variation and links with depressive symptoms

Background: We compare the genotype distribution for the serotonin transporter polymorphism (5‐HTTLPR) in a sample of older Taiwanese adults with samples of various racial and ethnic groups collected in other studies. We also explore interactions among sex, stressors, and 5‐HTTLPR genotype on depressive symptoms in our sample. Methods: Using a nationally representative sample of 984 Taiwanese aged 53 and older, we model depressive symptoms as a function of 5‐HTTLPR genotype and two classes of stressors: lifetime trauma and recent major life events. We test two‐ and three‐way interactions among stressors, 5‐HTTLPR, and sex. >Results: This sample exhibits higher frequency of S/S and lower frequency of L/L genotype than Western samples, but the distribution is comparable to those in East Asian populations. Nearly 9% carry an allele (XL) that has rarely been reported in the literature. Although the gene–environment (G×E) interaction with recent major life events is not significant, our results suggest that trauma has a worse effect on depressive symptoms for those with S/S or S/L genotype than for those who do not carry the S allele (P<0.05). We find no evidence that this G×E interaction varies by sex. Conclusions: Previous studies of this G×E interaction have been inconclusive, perhaps because interactions between genotype and stressful events are more prominent under extreme stressors. Our findings underscore the need to move beyond a bi‐allelic parameterization of the 5‐HTTLPR polymorphism and raise questions about why East Asian populations exhibit low rates of depression despite a high frequency of the S allele. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.