Norepinephrine Transporter Gene Research Articles

Norepinephrine Transporter Gene Variants and Remission From Depression With Venlafaxine Treatment in Older Adults.

The primary objective of this study was to investigate five putatively functional variants of the norepinephrine transporter (SLC6A2, NET) and serotonin transporter (SLC6A4, SERT) genes and remission in depressed older adults treated with venlafaxine. A secondary objective was to analyze 17 other variants in serotonergic system genes (HTR1A, HTR2A, HTR1B, HTR2C, TPH1, TPH2) potentially involved in the mechanism of action of venlafaxine. The sample included 350 adults age 60 or older with DSM-IV-defined major depressive disorder and a score of at least 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Participants received protocolized treatment with open-label venlafaxine, up to 300 mg/day for approximately 12 weeks, as part of a three-site clinical trial. Each individual was genotyped for 22 polymorphisms in eight genes, which were tested for association with venlafaxine remission (a MADRS score ≤10) and changes in MADRS score during treatment. After adjusting for multiple comparisons, NET variant rs2242446 (T-182C) was significantly associated with remission (odds ratio=1.66, 95% CI=1.13, 2.42). Individuals with the rs2242446 C/C genotype were more likely to remit (73.1%) than those with either the C/T (51.8%) or the T/T genotype (47.3%). Individuals with the C/C genotype also had a shorter time to remission than those with the C/T or T/T genotypes and had a greater percentage change in MADRS score from baseline to end of treatment (up to week 12). NET rs2242446/T-182C may serve as a biomarker to predict the likelihood of remission with venlafaxine in older adults with major depression. These findings may help to optimize antidepressant outcomes in older adults.

Functional genetic polymorphisms in dopaminergic transporters: Association with ADHD traits in the Indian probands

ObjectivesThe dopamine (DAT) and norepinephrine (NET) transporters, encoded by SLC6A3 and SLC6A2 genes, regulate neurotransmitters controlling motor activity, attention, mood swings, and stress induced anxiety, thus becoming targets for therapeutic intervention. We explored contribution of SLC6A3 (rs40184, rs2652511) and SLC6A2 (rs3785143, rs11568324) variants in Attention-deficit hyperactivity disorder associated traits. MethodsNuclear families with ADHD probands (N=200) and ethnically matched controls (N=180) were recruited based on the DSM-IV-TR. Behavioral traits were assessed by the Conners' Parent Rating Scale-revised. Genomic DNA obtained from peripheral blood leukocytes was subjected to PCR based amplification of target sites followed by restriction fragment length polymorphism and sequencing based analysis. Statistical analysis was performed by population as well as family-based methods. ResultsThe control population showed significant difference in allelic and genotypic frequencies for rs40184, rs2652511 and rs11568324 in comparison to other Asian populations. Family-based analysis exhibited preferential transmission of rs3785143 and rs11568324 “C” alleles (P=0.009 & 0.05). Gene variants showed association with behavioral problems and co-morbid disorders. Multifactor Dimensionality Reduction analysis revealed independent as well as synergistic effects of studied sites and phenotypic traits. ConclusionData obtained for the first time evidenced association of dopamine and norepinephrine transporter gene variants with phenotypic traits and co-morbidity of Indian ADHD probands.

Association of norepinephrine transporter gene polymorphisms in attention-deficit/hyperactivity disorder in Korean population

We investigated the association of three single nucleotide polymorphisms(SNP) of the norepinephrine transporter (NET) gene SLC6A2, T-182C (rs2242446), A-3081T (rs28386840), and G-1287A (rs5569) with the prevalence of attention-deficit/hyperactivity disorder (ADHD), its clinical severity, and other disease-related characteristics in a Korean population. The genotype, allele frequency and haplotype of 103 ADHD patients and 173 controls were analyzed for these three SNPs. All participants completed the Korean version of the ADHD Rating Scale (K-ARS). The ADHD group also completed the Korean Educational Development Institute-Wechsler Intelligence Scale for Children (KEDI-WISC) and the Continuous Performance Test (CPT) in a drug-naive state.The χ2 test and logistic regression analysis revealed no significant differences in the genotype distribution or allele frequencies of each SNP between the ADHD group and the control. In the haplotype analysis, the most common T-A-G haplotype was related to an increased risk of ADHD in females (P=0.002). There was no statistical significance between clinical features of ADHD and any specific allele of each SNP after multiple test correction except lower omission error in non-A girl carriers (GG type) of G-1287A (carrier 76.75±18.74, non-carrier 55.00±9.26, t=3.026, P=0.007, Bonferroni-corrected P=0.042). Some values related A-3081 and G-1287A showed a trend approaching the significance level when analyzed separately by gender. Even though it was not statistically meaningful after multiple test correction, G allele might have some protective effect against development of ADHD symptoms and this finding was consistent with previous studies.

P.3.b.028 - Gene polymorphism of neurotransmitter transporters in schizophrenic patients with drug-induced hyperprolactinemia

The regular therapy of schizophrenia includes a maintenance antipsychotic treatment, which improves the long-term prognosis of the disease [2]. Unfortunately antipsychotics also have a spectrum of side effects, including metabolic, endocrine and movement disorders [3,4]. One of the common side effects of these drugs is hyperprolactinemia (HP) [1]. The results of pharmacogenetic studies aimed at prognostic evaluation of the safe use of antipsychotics are the most persuasive. The components of dopamine, serotonin and norepinephrine neurotransmission in schizophrenia are considered as the main target for the action of antipsychotics. The present study aims to elucidate the role of 12 SNPs of dopamine transporter gene SLC6A3, 9 SNPs of norepinephrine transporter gene SLC6A2 and polymorphism of vesicular monoamine transporter gene SLC6A2 in the pathogenesis of antipsychotic-induced hyperprolactinemia in patients with schizophrenia. A total of 445 ethnic Russian patients from Siberia regions were studied, including 224 women and 221 men with a diagnosis of paranoid schizophrenia (the mean age - 42.1±1.4 years). Prolactin level was analyzed using the AccuBind ELISA Microwells kit (Monobind Inc., USA). Genotyping of SNPs was done with The MassARRAY® Analyzer 4 by Agena Bioscience™, using SEQUENOM. Statistical analysis was performed using the SPSS program. The Hardy-Weinberg equilibrium and differences in genotype frequencies were tested using a chi-square test. Differences were considered significant at p

Testing for the mediating role of endophenotypes using molecular genetic data in a twin study of ADHD traits.

Family and twin studies have identified endophenotypes that capture familial and genetic risk in attention‐deficit/hyperactivity disorder (ADHD), but it remains unclear if they lie on the causal pathway. Here, we illustrate a stepwise approach to identifying intermediate phenotypes. First, we use previous quantitative genetic findings to delineate the expected pattern of genetically correlated phenotypes. Second, we identify overlapping genetic associations with ADHD‐related quantitative traits. Finally, we test for the mediating role of associated endophenotypes. We applied this approach to a sample of 1,312 twins aged 7–10. Based on previous twin model‐fitting analyses, we selected hyperactivity–impulsivity, inattention, reading difficulties (RD), reaction time variability (RTV) and commission errors (CE), and tested for association with selected ADHD risk alleles. For nominally significant associations with both a symptom and a cognitive variable, matching the expected pattern based on previous genetic correlations, we performed mediation analysis to distinguish pleiotropic from mediating effects. The strongest association was observed for the rs7984966 SNP in the serotonin receptor gene (HTR2A), and RTV (P = 0.007; unadjusted for multiple testing). Mediation analysis suggested that CE (38%) and RTV (44%) substantially mediated the association between inattention and the T‐allele of SNP rs3785157 in the norepinephrine transporter gene (SLC6A2) and the T‐allele of SNP rs7984966 in HTR2A, respectively. The SNPs tag risk‐haplotypes but are not thought to be functionally significant. While these exploratory findings are preliminary, requiring replication, this study demonstrates the value of this approach that can be adapted to the investigation of multiple genetic markers and polygenic risk scores. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism.

Norepinephrine released from sympathetic nerves is removed from the neuroeffector junction via the action of the norepinephrine transporter (NET). NET impairment is evident in several clinically important conditions including major depressive disorder (MDD), panic disorder (PD), essential hypertension and the postural orthostatic tachycardia syndrome (POTS). We aimed to determine whether a single nucleotide polymorphism (SNP) in the 3' untranslated region (UTR) of the NET gene is associated with NET impairment and to elucidate the mechanisms involved. The analyses were carried out in two cohorts of European ancestry, which included healthy controls and MDD, PD, hypertensive and POTS patients. Compared with controls, cases had significantly higher prevalence of the T allele of rs7194256 (C/T), arterial norepinephrine, depression and anxiety scores, larger left ventricular mass index, higher systolic and diastolic blood pressures, and heart rate. Bioinformatic analysis identified that the microRNA miR-19a-3p could bind preferentially to the sequence created by the presence of the T allele. This was supported by results of luciferase assays. Compared with controls, cases had significantly lower circulating miR-19a-3p, which was associated with pathways related to blood pressure and regulation of neurotransmission. In vitro norepinephrine downregulated miR-19a-3p. In conclusion, the T allele of the rs7194256 SNP in the 3'UTR of the NET gene is more prevalent in diseases where NET impairment is evident. This might be explained by the creation of a binding site for the microRNA miR-19a-3p. A defect in NET function may potentiate the sympathetic neurochemical signal, predisposing individuals with affective diseases to increased risk of cardiovascular disease development.

A Prospective Study of Serotonin and Norepinephrine Transporter Genes and the Response to Desvenlafaxine Over 8 Weeks in Major Depressive Disorder

No studies to date have evaluated SLC6A2 and SLC6A4 genetic polymorphisms influencing antidepressant response to desvenlafaxine. We conducted an 8-week, open-label, prospective pilot study in 35 patients with major depressive disorder to assess the effects of genetic variations in SLC6A2 and SLC6A4 on both efficacy and side effect profile of desvenlafaxine. Results revealed that homozygotes for the SLC6A4 HTTLPR S allele showed a 33% HDRS reduction compared to a 58% reduction for L allele carriers (p=0.037). No results survived adjustments for covariates or multiple comparisons. While these results need to be interpreted cautiously, they provide preliminary support for the SLC6A4 HTTLPR polymorphism as potential modifier of desvenlafaxine efficacy.

Relationship between G1287A of the NET Gene Polymorphisms and Brain Volume in Major Depressive Disorder: A Voxel-Based MRI Study.

BackgroundEarlier studies implicated norepinephrine transporter (NET) gene (SLC6A2) polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide SLC6A2 polymorphisms, G1287A in exon 9 and T-182C in the promoter region, were found to be associated with MDD in different populations. We investigated the relationship between the brain volume and these two polymorphisms of the SLC6A2 in MDD patients.MethodsWe obtained 3D high-resolution T1-weighted images of 30 first-episode MDD patients and 48 age- and sex-matched healthy subjects (HS). All were divided into 4 groups based on polymorphism of either the G1287A or the T-182C genotype. VBM analysis examined the effects of diagnosis, genotype, and genotype-diagnosis interactions.ResultsDiagnosis effects on the brain morphology were found in the left superior temporal cortex. No significant genotype effects were found in the T-182C and the G1287A. A significant genotype (G1287A)–diagnosis interaction was found in the left dorsolateral prefrontal cortex. No significant genotype (T-182C)–diagnosis interaction effects were observed in any brain region.ConclusionsIn MDD patients there seems to be a relationship between the volume of the dorsolateral prefrontal cortex and polymorphism of the SLC6A2 G1287A gene.

Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET.

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)‐[18F]FMeNER‐D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI‐TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype‐dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (−3081 A/T) and a 5′‐untranslated region (5′UTR) SNP (−182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3′UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884–895, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Association between norepinephrine transporter gene polymorphism and decision-making processing in patients with cerebral infarction

Objective To investigate the association between norepinephrine transporter (NET) gene polymorphism and decision-making processing in patients with cerebral infarction. Methods A total of 145 patients with cerebral infarction and 188 normal controls were enrolled in our study. In all subjects, the polymerase chain reaction (PCR) for NET-T182C/G1287A polymorphism assay, gel electrophoresis, image analysis and enzymatic reaction, gene sequencing methods were used. The relationships of NET-T182C/G1287A genotypes and alleles with decision-making processing were analyzed in patients with cerebral infarction.All participants completed six kinds of choice situational problems. Results There were significant differences in genotype and allele frequencies of T182C and G1287A polymorphism in NET between the patients with cerebral infarction and control group(for NET-T182C: genotype, χ2=4.437, P=0.049, allele frequency, χ2=4.363, P=0.037, OR=0.625, 95%CI: 0.436-0.895; for NET-G1287A: genotype, χ2=8.435, P=0.038, allele frequency, χ2=2.765, P=0.036, OR=1.520, 95%CI: 1.053-2.193). The cerebral infarction patients with three NET-T182C genotypes and T/C alleles all completed six choice scenarios, and the scheme selection probability had no significant difference (all P>0.05). In high-risk and no-risk loss situation (scenario 4), the scheme selection probability had significant difference in cerebral infarction patients with NET-G1287A genotypes and G/A alleles (P 0.05). Conclusions NET-G1287A polymorphism may be associated with decision-making processing in patients with cerebral infarction. In the high-risk and no-risk loss condition, patients with GG genotype and G allele have more loss risk aversion. Key words: Brain infarction; Choice behavior; Norepinephrine plasma membrane transport proteins; Polymorphism, single nucleotide

A Genetic Susceptibility Mechanism for Major Depression: Combinations of polymorphisms Defined the Risk of Major Depression and Subpopulations.

Major Depression (MD) is a highly inherited psychiatric disorder. The norepinephrine transporter (NET) gene plays important role in pathophysiology of MD. This study attempted to examine the relationship between polymorphisms of NET gene and MD.Patients with MD and healthy controls were recruited and subgrouped. The T-182C and G1287A polymorphisms of NET gene were genotyped by direct sequencing. The genotypic and allelic frequencies were compared using the Pearson χ2 analysis. The linkage disequilibrium was analyzed using the UNPHASED program.Significant differences in genotypic and allelic frequencies of T-182C polymorphism were observed between MD subgroups and controls. When referenced by TT genotype, the OR value increased gradient from TC to CC genotype; when referenced by T allele, the odds ratio value of C allele also increased. Compared with those having both −182 T/T and 1287 G/G genotypes, in patients with MD, early-onset MD, and MD with suicide concept group, the −182 C/C and 1287 G/A combinatorial genotype has significant risk; yet in patients with MD family history, the −182 C/C and 1287 A/A combinatorial genotype has significant risk.Different combinations of T-182C and the G1287A polymorphisms of NET gene might increase morbidity risk of MD subpopulations.

Influence and interaction of genetic polymorphisms in norepinephrine transporter and enviroment on antidepressant drug response

Objective To determine how genetic polymorphisms in norepinephrine transporter(NET) gene influence the response of antidepressant treatment and how they interact with childhood trauma and recent life stress in a Chinese depressive patients. Methods 281 Chinese Han depressive patients received single antidepressant drugs for 6 weeks. Hamilton Depression Scale-17 (HAMD-17), the Childhood Trauma Questionnaire short term (CTQ-SF) and the Life Events Scale (LES) were used to evaluate severity of depressive symptoms and the occurrence of stressful life events respectively. Three single nucleotide polymorphisms (SNPs) in norepinephrine transporter were genotyped. Associations of single locus and haplotypes with antidepressant treatment response were analyzed using UNPHASED 3.0.13. The interaction of gene and life stress was analyzed by SPSS13.0 software. Results One NET SNP rs2242446 was significantly associated with antidepressant response in this Chinese male sample(0.4118 vs 0.2375, χ2= 7.046, P=0.0079, OR=0.445, 95%CI(0.243-0.815)), as was the haplotype C-G(rs2242446 and rs5569; χ2=5.886, P=0.0153, OR=0.457, 95%CI(0.198-1.054)) and another haplotype C-G-G(rs2242446, rs1532701 and rs5569; χ2=5.360, P=0.0206, OR=0.530, 95%CI(0.202-1.386)) of NET in male samples. The NET SNPs rs5569 demonstrated interaction with childhood trauma to influence antidepressant response(β=-2.727, SE=1.195, P=0.023, OR=0.065, 95%CI(0.006-0.681)). Conclusion Antidepressant drug response was influenced by not only NET genetic polymorphisms in norepinephrine transporter gene but also interaction between the NET genetic polymorphisms and early life stress. Key words: Antidepressant drugs; Gene; Environment; Norepinephrine transporter

Deficiency of Sustained Attention in ADHD and Its Potential Genetic Contributor MAOA

Objective: To investigate the genetic contributors to ADHD sustained attention deficit among noradrenergic genes responsible for the synthesis (dopamine-β-hydroxylase gene, DBH), transport (norepinephrine transporter gene, NET1), reception (alpha-2A adrenergic receptor gene, ADRA2A), and metabolism (monoamine oxidase A gene, MAOA) of noradrenalin (NE). Method: A total of 456 children with ADHD and 108 normal controls were included in a digit cancellation test (DCT). DNA was collected from 242 participants and genotyped for 14 single nucleotide polymorphisms (SNPs) of noradrenergic genes. Results: Compared with normal controls, children with ADHD showed a lower total score and higher mean error rate in the DCT, indicating poorer sustained attention function. Analysis of covariance showed an association between MAOA genotypes and ADHD performance in DCT, with poorer performance in risk allele carriers. No association was found for other noradrenergic genes. Conclusion: Children with ADHD presented with a sustained attention deficit compared with normal controls. The sustained attention deficit of children with ADHD may be associated with genetic variant of MAOA.

SERT and NET polymorphisms, temperament and antidepressant response

Background: The genetic variations in norepinephrine transporter (NET) and serotonin transporter (SERT) genes have been associated with personality traits, several psychiatric disorders and the efficacy of antidepressant treatment. Aims: We investigated the separate effects and possible interactions between NET T-182C (rs2242446) and SERT 5-HTTLPR (rs4795541) polymorphisms on selective serotonin reuptake inhibitors (SSRI) treatment response and temperamental traits assessed by the Temperament and Character Inventory (TCI) in a clinical sample of subjects with major depressive disorder (MDD). Methods: Our sample of 97 patients with major depression completed the 107-item TCI temperament questionnaire (version IX) at the initial assessment of the study and after 6 weeks of follow-up. All subjects received selective SSRI medications. Temperament dimension scores at baseline (1) and endpoint (2) during antidepressant treatment were analyzed between NET and SERT genotypes. Results: SS-genotype of 5-HTTLPR was associated with higher baseline Persistence scores than SL- or LL-genotype. A corresponding but weaker association was found at endpoint. No differences were found between 5-HTTLPR genotypes and other temperament dimensions and 5-HTTLPR genotypes had no effect on treatment response. Conclusions: Our results suggest that the SS-genotype of 5-HTTLPR is associated with Persistence scores in patients with MDD. Higher Persistence could be viewed as a negative trait when recovering from stress and its association with short and “weaker” S-allele may be related to less efficient serotonin neurotransmission, possibly resulting in less effective coping strategies on a behavioral level.

Differential regulation of catecholamine synthesis and transport in rat adrenal medulla by fluoxetine treatment.

We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.

Serotonin transporter (5-HTTLPR) and norepinephrine transporter (NET) gene polymorphisms: Susceptibility and treatment response of electroconvulsive therapy in treatment resistant depression

Serotonin transporter (5-HTTLPR) and norepinephrine transporter (NET182C) polymorphisms are associated with susceptibility and treatment response in major depressive disorder (MDD). Thus, we examined association between these polymorphisms and susceptibility to treatment resistant depression, and treatment response in severe MDD patients treated with electroconvulsive therapy (ECT).In total, 119 Finnish patients with treatment resistant depression and 395 healthy volunteer blood donors were genotyped. Depression severity was assessed using the Montgomery–Åsberg Depression Scale (MADRS), with MADRS score change during ECT the treatment response indicator.Underrepresentation of the 5-HTTLPR l/l genotype in the NET TT subgroup was observed in patients compared with controls. There were no genotype or allele frequency differences between patients and control groups separately. Patients with combined 5-HTTLPR l/l and NET TT genotypes also had poorer treatment responses than other patients. No differences in ECT response were observed when the polymorphisms were examined separately.Our results suggest that a NET 182C and 5-HTTLPR polymorphism interaction is associated with susceptibility to treatment resistant depression and ECT treatment response in antidepressant resistant depression patients.

Association Study between Norepinephrine Transporter Gene Polymorphism and Schizophrenia in a Korean Population.

ObjectiveWe aimed to investigate possible associations between three norepinephrine transporter gene (SLC6A2) single nucleotide polymorphisms (T182C, A3081T, and G1287A) and schizophrenia. Also, we investigated the relationships of those polymorphisms with clinical severity and characteristics of schizophrenia.MethodsParticipants were 220 schizophrenia patients in the acute phase and 167 healthy controls. The genotype, allele frequency, and haplotype of each group were analyzed for T182C, A3081T, and G1287A polymorphisms. Of the 220 schizophrenia patients, 163 patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Korean version of the Calgary depression scale for schizophrenia (K-CDSS) at baseline.ResultsWe found no significant differences between the schizophrenia patient group and the control group in genotype distribution or allele frequency of the three tested polymorphisms. Likewise, we could not find any significant differences in genotype or allele frequency by analyzing according to gender. In the haplotype study, no significant association emerged between specific haplotype combinations and schizophrenia. We also found no association between clinical scales (PANSS and K-CDSS) and the studied polymorphisms.ConclusionOur results suggest that the investigated polymorphisms of the NET gene are not associated with susceptibility to schizophrenia or its clinical features in a Korean population. However, this study remains significant because it is the first haplotype study to investigate associations between NET gene (SLC6A2) single nucleotide polymorphisms and schizophrenia in a Korean population. Future research with a larger sample size and more genetic markers is needed to replicate our results.

Analysis of Association between Norepinephrine Transporter Gene Polymorphisms and Personality Traits of NEO-FFI in a Japanese Population

ObjectiveNorepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger's theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger's personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model.MethodsAfter written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students.ResultsA significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms.ConclusionWe conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires.

A haplotype of the norepinephrine transporter gene (SLC6A2) is associated with visual memory in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common heritable childhood-onset psychiatric disorder with impaired visual memory. Based on the evidence from treatment effect of atomoxetine, which interacts directly with the norepinephrine transporter, on visual memory in children with ADHD, this study examined the linkage disequilibrium structure of the norepinephrine transporter gene (SLC6A2) and the association between SLC6A2 and ADHD and visual memory, a promising endophenotype for ADHD. This family-based association sample consisted of 382 probands with DSM-IV ADHD and their family members (n=1298 in total) of Han Chinese in Taiwan. Visual memory was assessed by the Pattern Recognition Memory (PRM) and Spatial Recognition Memory (SRM) tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We screened 21 polymorphisms across SLC6A2 and used the Family-Based Association Test (FBAT) to test the associations of SLC6A2 polymorphisms with ADHD and the PRM and SRM measures. In haplotype analyses, a haplotype rs36011 (T)/rs1566652 (G) was significantly associated with ADHD (minimal p=0.045) after adjustment for multiple testing. In quantitative analyses, this TG haplotype also demonstrated significant associations with visual memory measures, including mean latency of correct responses in PRM (minimal p=0.019), total correct responses in PRM (minimal p=0.018), and total correct responses in SRM (minimal p=0.015). Our novel finding of the haplotype rs36011 (T)/rs1566652 (G) as a novel genetic marker involved in both ADHD disease susceptibility and visual memory suggests that allelic variations in SLC6A2 could provide insight into the pathways leading from genotype to phenotype of ADHD.

SLC6A2 variants may predict remission from major depression after venlafaxine treatment in Han Chinese population

ObjectiveVenlafaxine, an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) type, is used to treat patients with major depressive disorder (MDD). Much evidence suggests that genetic polymorphisms may modulate serotonergic and noradrenergic function, thereby affecting the treatment efficacy of venlafaxine. The aim of this study was to examine whether polymorphisms in the norepinephrine transporter gene (SLC6A2) associate with remission after venlafaxine treatment for MDD. MethodAn 8-week naturalistic treatment study with venlafaxine was carried out in 243 Han Chinese patients with MDD. The patients were screened for seven single-nucleotide polymorphisms of the SLC6A2 gene. Of the enrolled patients, 161 completed the 8-week treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was used to assess the improvement of depressive symptoms in each subject from baseline to the endpoint. For better presentation of time-course change of remission status, a Cox regression analysis for remission incidence during the 8-week treatment was conducted. ResultsBetween remitters and non-remitters, significant differences in genotype frequencies were observed in five of the investigated SLC6A2 variants (rs28386840, rs1532701, rs40434, rs13333066, rs187714). GCG haplotype (rs40434－rs13333066－rs187714) in the SLC6A2 gene showed a association with non-remission. A Cox regression analysis for remission incidence during the 8-week treatment course significantly depends on SLC6A2 variants (rs28386840, rs40434, and rs187714). ConclusionOur results suggest that the variation of the SLC6A2 gene is associated with treatment remission after venlafaxine in patients with MDD.