Association of the serotonin transporter promoter region polymorphism with biased attention for negative word stimuli

Background: Biased attention for emotional stimuli reflects vulnerability or resilience to emotional disorders. The current study examines whether the 5‐HTTLPR polymorphism is associated with attentional biases for negative word stimuli. Methods: Unmedicated, young adults with low current depression and anxiety symptoms (N=106) were genotyped for the 5‐HTTLPR, including the single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5‐HTTLPR. Participants then completed a standard dot‐probe task that measured attentional bias toward anxiety, dysphoric, and self‐esteem words. Results: The L_AL_A allele group demonstrated an attentional bias away from negative word stimuli. This attentional bias was absent among the S/L_G carriers. Conclusions: These findings replicate previous work and suggest that 5‐HTTLPR L_A homozygotes possess a protective attentional bias that may decrease susceptibility to depression and anxiety. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

(11)C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET

The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.     

No association of serotonin transporter gene (SLC6A4) with schizophrenia and bipolar disorder in Japanese patients: association analysis based on linkage disequilibrium

Summary. Serotonin transporter gene (SLC6A4) is one of the most promising candidate genes for psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BP). Two functional polymorphisms, 5HTTLPR and 5HTTVNTR, have been a focus for genetic association analyses; however, no conclusive results have been obtained. We conducted, 1) a mutation search of SLC6A4, 2) LD mapping to select ‘tagging’ markers (10 SNPs and 5HTTVNTR, while 5HTTLPR was treated as an independent marker because of its allelic form), and 3) association analysis of these ‘tagging’ markers and independent markers (5HTTLPR and Asn605Lys) with SCZ and BP in Japanese patients. In this mutation search, a nonsynonymous SNP, Asn605Lys, was detected. No associations of ‘tagging’ markers and independent markers with such conditions were found. These results indicate that SLC6A4 might not play a major role in SCZ and BP in Japanese patients, a finding that agrees with both the common disease-common variant hypothesis and common disease-rare variant hypothesis.     

Positron emission tomography quantification of serotonin transporter binding in medication‐free bipolar disorder

Objectives: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5‐HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [¹¹C]DASB, we compared 5‐HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs). Experimental Design: 5‐HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of V_T/f_P (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt. Principal Observations: 5‐HTT binding (V_T/f_P) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BP_F*, BP_P*, and BP_ND*) indicated lower binding in BD compared with HV across these six regions of interest (BP_F*: P = 0.047; BP_P*: P = 0.032; BP_ND*: P = 0.031). 5‐HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder. Conclusions: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [¹¹C]DASB. We do not find evidence of abnormal 5‐HTT binding in bipolar depression using our primary outcome measure, V_T/f_P. However, we did observe lower 5‐HTT binding in BD with alternative outcome measures that are frequently used with [¹¹C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted. Synapse 70:24–32, 2016. . © 2015 Wiley Periodicals, Inc.     

Lack of association between the LPR and VNTR polymorphisms of the serotonin transporter gene and cocaine dependence in a Spanish sample

We genotyped the LPR and VNTR polymorphisms of the serotonin transporter gene in 504 cocaine-dependent patients and 508 controls. No association was detected with either polymorphism or with any haplotype combination. This study provided no evidence that these polymorphisms confer susceptibility to cocaine dependence in our sample.     

5-羟色胺转运体基因启动子区与心境障碍的关联分析

目的 探讨5-羟色胺转运体基因启动子区5-HTTLPR与心境障碍之间的分子遗传学联系。方法 在中国汉族人群中，以心境障碍核心家系作为研究对象，根据哈佛大学提供的遗传学研究用诊断性检查表(DIGS)自编家系调查表，采用DSM-Ⅳ诊断标准并结合一些心理测评工具，以达到表型一致。在72个情感性精神障碍核心家系，222个家系成员(其中双相障碍56例，重性抑郁症34例)中，应用聚合酶链反应(PCR)和限制性片段长度多态性方法，对5-HTT基因启动子区5-HTTLPR与心境障碍之间的分子遗传学联系进行了以家系为基础的连锁不平衡分析结果基因型和等位基因频率在心境障碍患病组和父母对照组之间无显著差异。GHRR和HHRR分析以及多等位基因ETDT统计分析也没有发现存在连锁不平衡。5-HTTLPR位点除了“L”和“S”片段外，还发现2例出现“L^*”(528^*bp)片段，频率约占1％。结论 5-HTYLPR在心境障碍的发病中可能不起重要作用。     

Serotonin‐transporter‐linked promoter region polymorphism and serotonin transporter binding in drug‐naïve patients with major depression

Aims: Both the serotonin transporter and its genetic regulation by the serotonin‐transporter‐linked polymorphic region have a role in the pathophysiology of depression. Most of the previous studies have found no influence of serotonin‐transporter‐linked polymorphic region allelic variation on serotonin transporter binding in healthy controls or patients with major depression. Due to the inconsistency of the previous findings, we compared single photon emission computed tomography imaging with the serotonin‐transporter‐linked polymorphic region genotype in patients with major depressive disorder. Methods: A total of 23 drug‐naïve patients with major depressive disorder were genotyped and brain imaged with ^[123I]nor‐β‐CIT single photon emission computed tomography. The severity of depression was evaluated with the 17‐item Hamilton depression rating scale. Results: Depressed patients homozygous for the short allele had lower ^[123I]nor‐β‐CIT binding in the medial prefrontal cortex, but not in the midbrain, compared with the other genotypes. Conclusion: The decreased medial prefrontal cortical serotonin transporter binding in the patients homozygous for the short allele may be linked to altered function of the serotonin‐transporter‐linked polymorphic region gene expressed in these patients, especially in the medial prefrontal cortex.     

Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety

OBJECTIVE: The objective of this study was to verify the hypothesis that variation of the serotonin transporter gene promoter region (5-HTTLPR) is associated with sensitivity to stress. METHODS: Genotyping of 5-HTTLPR and evaluation of emotional states were performed on 194 participants. Participants' emotional states were evaluated using the Perceived-Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Self-rating Depression Scale (SDS). RESULTS: There was significant GenderxGenotype interaction in STAI (state, P<.05; trait, P<.05). Females with the l/s genotype showed higher anxiety than those with the s/s genotype in both state and trait anxiety. Oppositely, males with the s/s genotype showed higher anxiety than those with the l/s genotype. CONCLUSION: On all emotional scales, females with the l/s genotype showed high scores, contrary to males with the same genotype. Therefore, our results suggest that 5-HTTLPR l allele may be one pathway that activates negative emotion in females but acts contrary in males.     

5-羟色胺转运体启动子区基因多态性与强迫症的关联分析

目的:探索汉族人群中的5-羟色胺转运体启动子区(5-HTTLPR)基因多态性与强迫症的发病关系.方法:对强迫症患者(强迫症组)和正常对照者(对照组)分别采用聚合酶链反应扩增片断长度多态技术测定基因型.结果:强迫症组与对照组5-HTTLPR的基因型频率无显著性差异;两组的等位基因频率有显著性差异.L等位基因与强迫症呈正关联(OR=1.929,P＜0.05).结论:5-HTTLPR基因多态性的L等位基因与强迫症相关联,是强迫症的危险因子.     

Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis.

BACKGROUND: There is strong evidence supporting a role for serotonin system dysfunction in the pathology of suicidal behavior. Many studies have examined the association between a functional polymorphism of the serotonin transporter gene promoter (5-HTTLPR) and suicide but have yielded inconsistent results. Our goal here, by analyzing the cumulative data from primary literature, was to determine conclusively whether there is an association. METHODS: Three meta-analyses were performed. One compared the 5-HTTLPR polymorphism between suicidal subjects and normal control subjects; another compared suicide attempters with nonattempters of the same psychiatric diagnoses; the last one compared either violent or nonviolent suicidal subjects with normal control subjects. RESULTS: We found no association between 5-HTTLPR polymorphism and suicidal behavior (p =.379). When we compared subjects with the same psychiatric diagnoses, the genotypes carrying the s allele were significantly more frequent in suicide attempters than in nonattempters (p =.004). In addition, the s allele was associated with violent suicide (p =.0001) but not with nonviolent suicide (p = 1.00). CONCLUSIONS: Our results provide significant evidence supporting the association of the s allele of 5-HTTLPR polymorphism with suicidal behavior in the psychiatric population, also with violent suicide. These support a role for decreased serotonin transporter function in the vulnerability to suicide in a select population.     

Possible association between serotonin transporter promoter region polymorphism and impulsivity in Koreans

Serotonin has become the major focus of biological studies of suicidal behavior and impulsive-aggressive behavior in humans. The serotonin transporter (5-HTT) gene is one of the important genes involved in the regulation of serotonin transmission. We examined the association of impulsivity in Korean populations with a functional polymorphism of the promoter region of the 5-HTT gene (5-HTTLPR). We recruited 186 adolescent prisoners and 64 medical students. Impulsivity was measured using the Barratt Impulsiveness Scale and we divided all subjects into three groups: impulsive subjects (IS, N=121), non-impulsive subjects (NIS, N=115) and an intermediate group (excluded, N=14). The 5-HTTLPR genotype was determined by polymerase chain reaction. All subjects were Korean men unrelated to each other. There were no significant differences in the genotype frequency of 5-HTTLPR-S/S, S/L and -L/L between the two groups in the Korean population (IS vs. NIS: 47.9 vs. 61.7%; 43.0 vs. 32.2%; and 9.1 vs. 6.1%, respectively). However, there was a statistically significant difference in allelic frequency of 5-HTTLPR-S and 5-HTTLPR-L between the two groups in the Korean population (IS vs. NIS: 69.4 vs. 77.8%; and 30.6 vs. 22.2%, respectively. From our results, this 5-HTTLPR polymorphism appears to be a possible candidate gene for impulsivity in the Korean population.     

Age‐related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence

The S and L_G alleles of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) lower serotonin transporter expression. These low‐expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala–prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces depression that emerges in adolescence, whereas decreased serotonin transporter that occurs later in development ameliorates depression. However, no brain imaging research has yet investigated the moderating influence of human development on the link between 5‐HTTLPR and effect‐related brain function. We investigated the age‐related effect of 5‐HTTLPR on amygdala activation and amygdala–prefrontal cortex connectivity using a well‐replicated probe, an emotional face task, in children and adolescents aged 9–19 years. A significant genotype‐by‐age interaction predicted amygdala activation, such that the low‐expressing genotype (S/S and S/L_G) group showed a greater increase in amygdala activation with age compared to the higher expressing (L_A/L_A and S/L_A) group. Additionally, compared to the higher expressing group, the low‐expressing genotype group exhibited decreased connectivity between the right amygdala and ventromedial prefrontal cortex with age. Findings indicate that low‐expressing genotypes may not result in the corticolimbic profile associated with depression risk until later adolescence. Hum Brain Mapp 35:646–658, 2014. © 2012 Wiley‐Periodicals, Inc.     

A novel allele in the promoter region of the human serotonin transporter gene

The human serotonin transporter (hSERT) gene is a promising candidate for mediating the genetic susceptibility for various psychiatric conditions such as mood and obsessive-compulsive disorders. Two polymorphic sites in this gene attracted much interest: a VNTR of 17-bp repeats in intron two, and an insertion/deletion in the 5'-flanking promoter region (5-HTT gene-linked polymorphic region-5-HTTLPR) creating a short (S) and a long (L) allele. The 5-HTTLPR polymorphism is situated in a GC-rich region composed of 20-23 bp repeating units. The S and L alleles have 14 and 16 repeat-elements respectively. Positive associations of the 5-HTTLPR polymorphism with mood disorders, anxiety-related personality traits, autism and late-onset Alzheimer's disease have been published, although some non replications were also reported. Here we report a novel allele (termed LJ) in the 5-HTTLPR site. This allele is longer than the L allele by 43 bp, has 18 repeat units and contains two copies of the insertion/deletion sequence arranged in tandem. The LJ allele was found in individuals of Libyan and Tunisian Jewish origin but not in Moroccan or Ashkenazi Jews.     

No association of a functional polymorphism in the serotonin transporter gene promoter and anxiety-related personality traits

Serotonergic neurotransmission, which is involved in many psychiatric disorders, is mediated by the serotonin transporter protein. Gene coding for the serotonin transporter protein is designated SLC6A4, which has been differentially associated with anxiety-related behavioral traits and neuroticism in healthy subjects. To confirm the association between the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) and anxiety-related personality traits, we examined 228 healthy unrelated participants (age 38.6 +/- 12.8 years; 115 male, 113 female) of German origin, who were carefully examined with respect to psychiatric health. The self-ratable State-Trait Anxiety Inventory (STAI) and the NEO Five Factor Inventory (NEO-FFI) were performed. No significant association was observed between the 5-HTTLPR genotype and STAI 1 (state, chi2 = 0.82, p < 0.66, d.f. = 2), STAI 2 (trait, chi2 = 2.7, p < 0.25, d.f. = 2) and NEO-FFI scores of any of the 5 major axes, including neuroticism (chi2 = 3.35, p < 0.18, d.f. = 2) in all subjects. Given the small effect of this 5-HTT polymorphism on behaviour in previous studies, a lack of significant genotype differences in these tests could be due to considerable individual variability in these measures.     

Relationships between serotonin transporter promoter polymorphism, platelet serotonin transporter binding and clinical phenotype in suicidal and non-suicidal adolescent inpatients

Summary. Relationships between the serotonin transporter promoter polymorphism (5-HTTLPR), platelet serotonin transporter (SERT) binding and clinical phenotype were examined in 32 suicidal and 28 non-suicidal Ashkenazi Israeli adolescent psychiatric inpatients. The 5-HTTLPR polymorphism was not associated with transporter binding or with suicidality or other clinical phenotypes. However, in the suicidal group, a significant positive correlation between platelet SERT density and anger scores (n=32, r=.40; p=.027) and a negative correlation between platelet count and trait anxiety (n=32, r=–.42; p=.034) were observed.     

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism.

BACKGROUND: A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS: SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS: Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS: Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.