Association between the serotonin transporter gene and alcohol consumption in social drinkers.

Relatively few studies have investigated the role of the 5HTT gene in intermediate phenotypes such as alcohol consumption in non-alcohol dependent populations. A recent study reported an association with alcohol consumption in a student population. We attempted to replicate these findings and extend on this work in a representative, ethnically homogenous, non-alcohol dependent sample of social drinkers in the United Kingdom. The short allele of the 5HTT gene was significantly associated with increased alcohol consumption (P = 0.03). There was suggestive evidence of a genotype-sex interaction (P = 0.04). Post-hoc tests indicated higher alcohol consumption in men with one or more copies of the short allele, while in women consumption was highest among heterozygotes compared to both homozygote groups. Age at time of data collection and cigarette consumption were entered as covariates. These results replicate recent previous findings and suggest a possibility that this association may differ in men and women.     

The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression

BACKGROUND: Serotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression. METHOD: We typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype. RESULTS: There were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction. CONCLUSIONS: Regardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.     

Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission and is thought to influence emotion. A 5-HTT-linked polymorphic region (5-HTTLPR) has two common variants, short (s) and long (l). We previously found population and within-family associations between the lower-expressing s allele and neuroticism, a trait related to anxiety, hostility, and depression, on a standard measure (the NEO Personality Inventory, Revised [NEO-PI-R]) in a primarily male population (n=505), and that the s allele was dominant. We investigated this association in a new sample (n=397, 84% female, primarily sib-pairs). The results robustly replicated the 5-HTTLPR neuroticism association, and the dominance of the s allele. Combined data from the two studies (n=902) showed a highly significant association between the s allele and higher NEO Neuroticism both across individuals and within families. Association between genotype and a related measure, Anxiety on the 16PF inventory, was replicated in the new population and within families in the combined sample. Association to another trait, estimated TPQ Harm Avoidance, was not replicated in the new sample but found only within the combined sibship group. Another association found in our original study, between the s allele and lower scores on NEO-PI-R Agreeableness, was also replicated and was more robust in the current and the combined samples. Associations between the functional 5-HTTLPR polymorphism were similar in women and men. These results help to define specific personality features reproducibly associated with 5-HTTLPR genotype. Such associations were strongest for traits defined by the NEO, enhancing the attractiveness of the five-factor personality model in genetic research on complex behavioral dimensions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:202-216, 2000. Published 2000 Wiley-Liss, Inc.     

Association between serotonin transporter gene polymorphisms and depressed mood caused by job stress in Japanese workers

To estimate the genetic factors influencing depressed mood caused by job stress, a total of 243 employees at a manufacturing company and a local hospital in Japan (mean age 40.8+/-10.3 years) were recruited with informed consent. The Brief Job Stress Questionnaire was used to assess the present status of stress. Alcohol consumption and smoking were assessed as lifestyle factors. DNA samples were prepared to detect gene polymorphisms of serotonin transporter (5HTT), aldehyde dehydrogenase 2, D2 dopamine receptor, and cytochrome p450 2A6. The relationship between job stress, lifestyle factors and these polymorphisms was assessed for each gender. The level of depressed mood for female subjects was significantly higher among the carriers of two short (s/s) alleles of the 5HTT regulatory region compared with the carriers of one (s/l) or two (l/l) long alleles (Mann-Whitney U test, p<0.05). The odds ratio of depressed mood also confirmed this relationship for the female subjects, whereas there was no relationship for the male subjects. When social support was taken into consideration, the depressed mood score for those who had high support was significantly lower than for those who had low support, irrespective of 5HTT polymorphisms and gender. Job stress may elicit biological responses that contribute to depressed mood in relation to 5HTT polymorphisms, and social support may reduce depressed mood irrespective of 5HTT polymorphisms.     

Relationship between serotonin transporter gene polymorphisms and platelet serotonin transporter sites among African-American cocaine-dependent individuals and healthy volunteers

Alterations in the serotonin transporter (5-HTT) have been implicated in a variety of psychiatric disorders including cocaine dependence. A polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) appears to influence the expression of 5-HTT in human cell lines. We investigated whether 5-HTTLPR variants were related to differences in measures of platelet 5-HTT sites in cocaine-dependent patients and healthy volunteers (controls). Polymerase chain reaction-based genotyping of a 44 base pair insertion/deletion polymorphism in 5-HTTLPR was performed in 138 cocaine-dependent African-American subjects and 60 African-American controls. This yielded a short (S) and a long (L) allele. Platelet 5-HTT sites were measured using the tritiated paroxetine binding assay. Relationships of 5-HTTLPR genotypes with Bmax (density of serotonin transporter) and Kd (affinity constant) were examined. Bmax values were significantly lower in cocaine-dependent patients (640 +/- 233) than controls (906 +/- 225) (P < 0.001); however, 5-HTTLPR genotype distributions or allele frequencies did not differ between the two groups. There were no significant differences in Bmax between the three genotypes among cocaine-dependent patients (LL = 690 +/- 246, LS = 620 +/- 235, SS = 587 +/- 183; P = 0.14) or controls (LL = 909 +/- 233, LS = 938 +/- 279, SS = 866 +/- 143; P = 0.65). All three genotypes in cocaine-dependent patients showed comparable reductions in Bmax from the corresponding genotypes in controls. Demographic variables, severity of substance use or depression were unrelated to Bmax or 5-HTTLPR genotypes. Although platelet 5-HTT densities are reduced in patients with cocaine dependence compared with healthy volunteers, these genotypic variations in the serotonin transporter do not seem to influence levels of platelet 5-HTT in cocaine-dependent patients or healthy volunteers.     

Association between serotonin transporter gene polymorphism and eating disorders outcome: a 6-year follow-up study

Eating disorder patients show different long-term outcomes, and trait-related alterations of serotonergic function, which might be related with the serotonin transporter (5-HTT) gene. We studied the relationships between 5-HTTLPR polymorphism, eating specific and general psychopathology and the long-term outcome of anorexia nervosa (AN) and bulimia nervosa (BN) patients. We evaluated the distribution of the functional 5-HTTLPR polymorphism in a series of 201 Italian, Caucasian, eating disorder patients (113 with AN and 88 with BN binge/purging (BP subtype) and in 150 Caucasian unrelated controls. Prior to starting an individual cognitive behavior therapy, a clinical assessment was performed by means of the structured clinical interview for DSM-IV axis I disorders and several self-report questionnaires. This assessment was repeated at the end of treatment, 3 years after the end of treatment and 3 years after the first follow-up. Diagnostic changes between AN and BN were frequent (28.3%), and the presence of depressive disorders was associated with a higher rate of diagnostic crossover during the follow-up period. The S-allele of the 5-HTTLPR genotype increases the risk susceptibility for both depressive comorbidity (OR?=?4.23; 95% CI, 1.45-12.37) and diagnostic crossover during the follow-up period in AN patients (OR = 5.04; 95% CI, 1.69-14.98). Logistic regression analyses confirmed these findings, when the interaction between genotype and psychiatric comorbidity as predictors of diagnostic instability in AN patients were taken into account. No significant association was found between 5-HTTLPR genotype and recovery. The S-allele of the 5-HTTLPR genotype increases the risk for depressive disorders comorbidity, and moderates the long-term outcome of anorectic patients.     

Association of the serotonin transporter gene, neuroticism and smoking behaviours

Cigarette consumption and smoking cessation are influenced in part by genes. Personality traits have also been implicated in the aetiology of smoking. Neuroticism, a personality trait with a heritable component, correlates well with anxiety and depression, increasing the risk of being a smoker and decreasing the chance of smoking cessation. Several prior studies in non-British populations have given conflicting results as to whether some genetic polymorphisms affect the relationship between smoking and neuroticism. This study investigated the influence of serotonin transporter (5HTTLPR) genotypes on a composite measure of neuroticism and cigarette consumption/smoking cessation in a British population. Although neuroticism was significantly associated with cigarette consumption and smoking cessation, genotype did not affect this relationship. Our results do not support initial interest in utilising 5HTTLPR genotypes in combination with neuroticism ratings for predicting outcome in smoking cessation clinical settings.     

Association study of serotonin transporter gene regulatory region polymorphism and alcoholism

Previous studies have indicated associations between a functional biallelic repetitive element in the 5′ regulatory region of the serotonin transporter gene (5‐HTTLPR) and alcoholic subjects who have either dissocial personality disorder or severe withdrawal symptoms. To replicate these associations under the hypothesis that genetic polymorphism plays some role in the susceptibility or vulnerability of some subgroup of alcoholics, the associations between alcoholic subjects' genetic polymorphisms, clinical characteristics, and personality traits were examined. This case control study comprised 697 alcoholic and 270 control subjects. A questionnaire focusing on family and social background, history of drinking and alcohol withdrawal, DSM‐III‐R criteria for the evaluation of psychiatric conditions, and Feighner's criteria for the lifetime diagnosis and assessment of overall severity of alcoholism was administered to 373 alcoholic subjects. Temperament and Character Inventory (TCI) and Sensation Seeking Scale (SSS) were used to evaluate the other 324 alcoholics. The frequency of the homozygous short allele was significantly higher in alcoholic binge drinkers than in nonbinge drinking alcoholics. There were no significant differences in the frequencies of either the 5‐HTTLPR genotype or the short vs. long allele in alcoholic and control subjects. The alcoholics' 5‐HTTLPR genotype and allele frequencies did not differ significantly by the severity of withdrawal symptoms or by the number of positive Feighner's diagnostic criteria. Although these results indicate an association between 5‐HTTLPR and a subgroup of alcoholics characterized by binge drinking, the authors found no differences in SSS and TCI subscale scores for alcoholics with different 5‐HTTLPR genotypes. Future studies of the association in other alcoholic population should take into account personality traits. © 2001 Wiley‐Liss, Inc.     

Association study of serotonin transporter gene regulatory region polymorphism and alcoholism.

Previous studies have indicated associations between a functional biallelic repetitive element in the 5' regulatory region of the serotonin transporter gene (5-HTTLPR) and alcoholic subjects who have either dissocial personality disorder or severe withdrawal symptoms. To replicate these associations under the hypothesis that genetic polymorphism plays some role in the susceptibility or vulnerability of some subgroup of alcoholics, the associations between alcoholic subjects' genetic polymorphisms, clinical characteristics, and personality traits were examined. This case control study comprised 697 alcoholic and 270 control subjects. A questionnaire focusing on family and social background, history of drinking and alcohol withdrawal, DSM-III-R criteria for the evaluation of psychiatric conditions, and Feighner's criteria for the lifetime diagnosis and assessment of overall severity of alcoholism was administered to 373 alcoholic subjects. Temperament and Character Inventory (TCI) and Sensation Seeking Scale (SSS) were used to evaluate the other 324 alcoholics. The frequency of the homozygous short allele was significantly higher in alcoholic binge drinkers than in nonbinge drinking alcoholics. There were no significant differences in the frequencies of either the 5-HTTLPR genotype or the short vs. long allele in alcoholic and control subjects. The alcoholics' 5-HTTLPR genotype and allele frequencies did not differ significantly by the severity of withdrawal symptoms or by the number of positive Feighner's diagnostic criteria. Although these results indicate an association between 5-HTTLPR and a subgroup of alcoholics characterized by binge drinking, the authors found no differences in SSS and TCI subscale scores for alcoholics with different 5-HTTLPR genotypes. Future studies of the association in other alcoholic population should take into account personality traits.     

Coaction of stress and serotonin transporter genotype in predicting aggression at the transition to adulthood

Despite consistent evidence that serotonin functioning affects stress reactivity and vulnerability to aggression, research on serotonin gene-stress interactions (G × E) in the development of aggression remains limited. The present study investigated variation in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress-aggression association at the transition to adulthood. Multiple informants and multiple measures were used to assess aggression in a cohort of 381 Australian youth (61% female, 93% Caucasian) interviewed at ages 15 and 20. At age 20, semistructured interviews assessed acute and chronic stressors occurring in the past 12 months. Structural equation modeling analyses revealed a significant main effect of chronic stress, but not 5-HTTLPR or acute stress, on increases in aggression at age 20. Consistent with G × E hypotheses, 5-HTTLPR short allele carriers demonstrated greater increments in aggression following chronic stress relative to long allele homozygotes. The strength of chronic stress G × E did not vary according to sex. Variation at 5-HTTLPR appears to contribute to individual differences in aggressive reactions to chronic stress at the transition to adulthood.     

No association between serotonin transporter gene polymorphisms and personality traits

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:430–436, 1999. © 1999 Wiley-Liss, Inc.     

The winner and loser effect, serotonin transporter genotype, and the display of offensive aggression

Aggressive behaviour results from a complex interplay between genetic and environmental factors. Key modulators of aggression include the serotonergic system on the molecular level and experience in prior aggressive contests as an environmental factor. The aim of this study was to elucidate the effects of fighting experience on the display of offensive aggressive behaviour in adult male mice varying in serotonin transporter (5-HTT) genotype. 5-HTT +/+, 5-HTT +/− and 5-HTT −/− mice were given either a winning or a losing experience on each of three consecutive days and were subsequently observed for their offensive aggressive behaviour as residents against a docile intruder from the C3H strain in a resident-intruder paradigm. The main findings were: There was no significant difference between the amount of offensive aggressive behaviour displayed by the genotypes. Winners showed more engagement with the intruder, attacked him faster and exhibited overall higher aggression scores than losers. There was no significant genotype × social experience interaction: winning and losing had a similar effect on offensive aggressive behaviour in all three 5-HTT genotypes.We conclude that social experience in terms of having been a winner or having been a loser rather than the 5-HTT genotype determines the behaviour towards a docile intruder.     

5-羟色胺和去甲肾上腺素转运蛋白基因多态性与抑郁症易感性的关联分析

7)之间存在显著性关联.结论 NET-T182C与抑郁症易感性存在关联,NET-T182C和5-HTTLPR均与抑郁症的严重程度存在关联.     

睡眠呼吸暂停综合征与5-羟色胺转运体基因多态性的关联分析

目的 初步探讨睡眠呼吸暂停综合征（sleep apnea syndrome，SAS）的遗传易感因素。方法 采用聚合酶链反应技术，检测104例SAS患者和150名健康对照者的5．羟色胺转运体（5-hydroxytryptamine transporter，5-HTT）基因启动子的基因连锁多态区（gene-hnked polymorphic region，LRR）和第2内含子的可变数目串联重复区（variable number tandem repeat，VNTR）多态性，分别对所得基因型和等位基因的频率进行相关统计学分析。结果 SAS患者5-HTT LPR多态性的基因型和等位基因频率与正常对照组之间的差异无统计学意义（P〉0．05）。SAS患者的5-HTT-VNWR的基因型10／10、12／10频率高于正常对照组（P〈0．05），其等位基因10的频率高于正常对照组（P〈0.01，OR=2.536，95％ CI：1．071～6．783）。结论 5-HTILPR可能不是SAS患者的遗传位点，第2内含子VNTR的等位基因10可能与SAS有一定的关联。     

No association between serotonin transporter gene polymorphisms and personality traits.

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study.     

Association of the serotonin transporter gene with serum cholesterol levels and heart disease.

In a study of a group of elderly athletes we observed an unexpected association between serum cholesterol levels and the HTTLPR insertion/deletion polymorphism of the promoter region of the serotonin transporter gene (HTT, SLC6A4). As a follow-up we examined the potential association of this polymorphism with cholesterol and triglyceride levels, or heart disease, in two other groups of subjects. We examined the possible association between cholesterol levels and heart disease and genotypes of the HTTLPR insertion/deletion polymorphism of the promoter region of the HTT gene, in three independent study populations ranging from 42 to 90 years of age. For subjects 55 to 70 years of age in Group 1, cholesterol levels were significantly greater in the LS heterozygotes than either LL or SS homozygotes, indicating a heterosis effect (P 70 years of age. While these studies are preliminary and exploratory, they are consistent with a relationship of the HTT gene in cholesterol levels and a risk for heart disease. Replication of these findings in independent, epidemiologically based studies is required.     

Association between the recombinant human serotonin transporter linked promoter region polymorphism and behavior in rhesus macaques during a separation paradigm

Human studies have suggested an association between a variable length polymorphism in the serotonin transporter gene promoter region and vulnerability to anxiety and depression. Relative to the long (l) allele, the short (s) allele increases the risk of developing depression in individuals exposed to stressful life events. An orthologue of the human variant is present in rhesus macaques and allows for studies in animals exposed to stress. Here, we used an established model of early life stress exposure, in which rhesus macaques are raised without adults in a group of peers (peer-only reared [PR]), or with their mothers. At 6 months of age, animals were subjected to 4-day long social separations for 4 consecutive weeks, with 3 days of reunion in between. Data were collected during both the acute (Day 1) and chronic phases (Days 2-4) of separation. Behavioral factors were separately extracted for each phase of separation. For acute separation, the behavioral factors generated were despair and behavioral pathology and, for the chronic phase despair, agitation, and behavioral pathology. During both phases of social separation, PR l/s animals were more likely to exhibit pathological behaviors, whereas PR l/l monkeys show higher levels of despair compared to the other three groups. These findings indicate that early stress affects the behavioral response to separation differently as a function of recombinant human serotonin transporter linked polymorphic repeat genotype and suggest that carriers of the s allele are not only more anxious but may also be more vulnerable to developing behavioral pathology in the face of chronic adversity.     

Association of a functional serotonin transporter gene polymorphism with binge eating disorder.

The pathophysiological mechanisms underlying binge eating disorder (BED) are poorly understood. There is evidence that abnormalities in brain serotonin (5HT) play an important role in binge eating behavior, therefore genes involved in 5HT transmission, such as the 5HT transporter (5HTT) gene, may contribute to the biological vulnerability to BED. We examined whether the polymorphism of the promoter of the 5HTT gene, consisting of a long (L) and a short (S) variant, was associated with BED. Seventy-seven obese or non-obese women with BED, and 61 normal weight control women were genotyped at the 5HTT gene linked polymorphism (5HTTLPR). Statistical analysis showed that both the LL genotype and the L allele of the 5HTTLPR were significantly more frequent in BED subjects. Moreover, the L allele was associated with a moderate but significant risk to develop BED (OR = 2.01, CI = 1.33-3.57). Although these data should be regarded as preliminary because of the small size of our sample, they suggest that the 5HTTPRL may contribute to the genetic susceptibility to BED.     

Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents.

Serotonin transporter promoter polymorphism (5-HTTLPR) genotype was previously found associated with smoking behavior, difficulty in quitting smoking, and nicotine addiction; with non-replicated findings and contrasting results. Aim of the present study was to evaluate the possible association between 5-HTTLPR genotype and smoking behavior among adolescents, in relationship with psychological characteristics. Two hundred and ten Caucasian high school students (aged 14-19 years); 103 non-smokers, who have never smoked nicotine; and 107 tobacco smokers have been genotyped. Aggressiveness levels and temperamental traits were measured in both smokers and non-smokers, respectively, utilizing Buss-Durkee Hostility Inventory (BDHI) and Cloninger Three-Dimensional Personality Questionnaire (TPQ). Data about school performance have been also collected. The short-short (SS) genotype frequency was significantly higher among smokers compared with non-smokers (P = 0.023). The odds ratio for the SS genotype versus the long-long (LL) genotype frequency was 1.17 [95% CL (0.30-2.05)], when smokers were compared with non-smokers. The SS genotype frequency was significantly higher among heavy smokers with early onset, compared with moderate smokers with late onset (P = 0.042). BDHI irritability scores, NS scores at TPQ, and school failure frequency were significantly higher in smokers than in non-smokers. Multivariate model-fitting analysis evidenced a significantly greater relationship of genotype with irritability levels (BDHI scores) (0.34, P < 0.001) and temperament traits (NS scores) (0.36, P < 0.001), than with school performance (rate of school under-achievements) (0.18, P < 0.05) and nicotine smoking (number of cigarettes) (0.24, P < 0.01). Accordingly, factor-analysis showed that gene polymorphism contributes more directly to BDHI scores and NS scores (0.73; 0.71) than to smoking behavior and school under-achievement (0.54; 0.51). Our data suggest that a decreased expression of the gene encoding the 5-HTT transporter, due to "S" promoter polymorphism, may be associated with smoking behavior among adolescents and increased risk to develop nicotine dependence, possibly in relationship to personality traits, temperamental characteristics, and school under-achievements.