Norepinephrine Transporter Gene Research Articles

Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD.MethodsThis study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I) score, and the ADHD Rating Scale-IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment.ResultsWe found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment.ConclusionOur findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD.

Dopamine, norepinephrine and serotonin transporter gene deletions differentially alter cocaine-induced taste aversion

Although cocaine is primarily known for its powerful hedonic effects, there is evidence that its affective experience has a notable aversive component that is less well understood. A variety of pharmacological and molecular approaches have implicated enhanced monoamine (MA) neurotransmission in the aversive effects of cocaine. Although numerous studies have yielded data supportive of the role of the monoamines (indirectly and directly), the specific system suggested to be involved differs across studies and paradigms (Freeman et al., 2005b; Grupp, 1997; Roberts and Fibiger, 1997). Monoamine transporter knockout mice have been useful in the study of many different aspects of cocaine effects relevant to human drug use and addiction, yet an assessment of the effects of deletion of the genes for the dopamine, norepinephrine and serotonin transporters (DAT, NET, and SERT, respectively) on cocaine's aversive properties has yet to be performed (Uhl et al., 2002). In the current investigation, the strength of cocaine-induced aversions was compared among three groups of transgenic mice with deletions of the genes responsible for the production of one of the monoamine transporters. When compared to their respective WT controls, dopamine transporter deletion slightly attenuated cocaine-induced aversion while deletion of SERT or NET resulted in a more significant delay in the onset and strength of cocaine-induced taste aversions. The data lead us to conclude that the action of cocaine to inhibit NET contributes most substantially to its aversive effects, with some involvement of SERT and minimal contribution of DAT.

Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression

Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, nerve growth factor, and neurotrophin-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NET knock out (NETKO) mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants.

Further evidence of association between amphetamine response and SLC6A2 gene variants

We previously found that the intronic norepinephrine transporter gene (SLC6A2) polymorphism rs36017 modulates feelings of elation after administration of 20 mg D-amphetamine in healthy volunteers. In this study, we further investigated the association between D-amphetamine response and 11 SLC6A2 single-nucleotide polymorphisms (SNPs), including rs36017, in an extended sample of Caucasian young adults. One hundred fifty-nine healthy volunteers participated in a three-session double-blind crossover design receiving either placebo or oral D-amphetamine (10 and 20 mg). Based on our previous results, we examined the associations between levels of self-reported elation and vigor after D-amphetamine administration and SNPs and SNP haplotypes in SLC6A2. Consistent with our previous findings, SNPs rs36017 and rs1861647 were associated with significantly higher ratings of elation and vigor after 20 mg Damphetamine. Ratings of vigor after 20 mg D-amphetamine were also associated with a two-SNP haplotype formed with rs1861647 and rs5569 and a three-SNP haplotype formed with rs36017, rs10521329, and rs3785155. These results provide further evidence that genetic variants in the SLC6A2 gene are involved in acute response to D-amphetamine, which may influence progression to amphetamine abuse. Identifying sources of variation in acute drug responses could lead to better prevention and treatment of psychostimulant abuse and may be valuable in the therapeutic use of stimulants.

Association of serotonin and norepinephrine transporter gene polymorphisms with the susceptibility to depression

To determine whether the serotonin transporter (5-HTT) and norepinephrine transporter (NET) gene polymorphisms were associated with the susceptibility to depression. Five hundred and seventy-nine patients with depression, evaluated using a 17-item Hamilton Depression Rating Scale for Depression (HAMD), and 437 healthy controls, all of Chinese Han origin, were genotyped by polymerase chain reaction. Both genotype distributions (P=0.033) and allele frequencies (P=0.023, OR = 1.250, 95% CI = 1.031-1.517) of NET-T182C were significantly different between patients and controls, where the T allele was associated with the onset of depression. Both NET-T182C T- and 5- HTTLPR L-carriers had higher baseline HAMD scores (P=0.032 and 0.023, respectively). There was an interaction between NET-T182C and 5-HTTLPR, where the combined genotype distributions were associated with both onset of depression (P=0.006) and the baseline HAMD scores (P=0.007). This study suggested a positive relationship between the NET-T182C polymorphism and the susceptibility to depression, and a positive relationship between NET-T182C/5-HTTLPR polymorphisms and the severity of depression.

Influence of serotonergic/noradrenergic gene polymorphisms on nausea and sweating induced by milnacipran in the treatment of depression

The present study was conducted to find out the predictors of side effects such as nausea and excessive sweating induced by milnacipran, a serotonin/norepinephrine reuptake inhibitor. Both clinical characteristics prior to the treatment and gene polymorphisms such as serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the second intron of the 5-HTT gene (5-HTTVNTR), 5-HT2A receptor gene (5-HT2A G-1438A), a TPH gene polymorphism in intron 7 (TPH A218C), norepinephrine transporter (NET) gene polymorphism in the promoter region (NET T-182C) and in the exon 9 (NET G1287A), a variable number of tandem repeats in the promoter region of monoamine oxidase A, were items to be assessed in this study. Ninety-six patients with major depressive disorder were treated with milnacipran. Side effects were assessed at 1, 2, 4, and 6 weeks of treatment with Udvalg for Kliniske Undersogelser side effects scale. The results showed that no gene polymorphisms included in this study affected the susceptibility of nausea and excessive sweating induced by milnacipran. Patients with older age are more likely to develop excessive sweating than others. The major limitation of this study is a small sample size. Further studies with larger populations and more kinds of gene polymorphisms should be needed to see if specific gene polymorphisms determine the susceptibility of side effects induced by milnacipran.

The norepinephrine transporter gene modulates the relationship between urban/rural residency and major depressive disorder in a Chinese population

The norepinephrine transporter (NET), which is involved in the neurotransmission of norepinephrine (NE), may play an important role in the development of major depressive disorder (MDD). Recent studies have suggested that a gene–environment interaction may confer susceptibility to depression. The aims of this study were to test modifying effects of the NET gene on the association between residency and MDD, as well as to reveal the relationship between gender and this gene-environment interaction in MDD. This study recruited a total of 442 patients with MDD and 393 controls. Residence was defined as reported in the data of the 5th Chinese census. Logistic regression models were used to analyze gene–environment interactions. A gene–environment interaction between the G1287A polymorphism and residency was found in the female sample. In addition, and odds ratio analysis showed that only rural women carrying the G/G genotype of the G1287A polymorphism were susceptible to MDD, but others were not. To our knowledge, this is the first report showing that the G1287A polymorphism modifies rural residency as a risk factor for MDD. These findings support the possibility that the NET gene is an important factor in susceptibility to MDD in a Han Chinese population.

A Novel Recombinant Vaccinia Virus Expressing the Human Norepinephrine Transporter Retains Oncolytic Potential and Facilitates Deep-Tissue Imaging

Noninvasive and repetitive monitoring of a virus in target tissues and/or specific organs of the body is highly desirable for the development of safe and efficient cancer virotherapeutics. We have previously shown that the oncolytic vaccinia virus GLV-1h68 can target and eradicate human tumors in mice and that its therapeutic effects can be monitored by using optical imaging. Here, we report on the development of a derivative of GLV-1h68, a novel recombinant vaccinia virus (VACV) GLV-1h99, which was constructed to carry the human norepinephrine transporter gene (hNET) under the VACV synthetic early promoter placed at the F14.5L locus for deep-tissue imaging. The hNET protein was expressed at high levels on the membranes of cells infected with this virus. Expression of the hNET protein did not negatively affect virus replication, cytolytic activity in cell culture, or in vivo virotherpeutic efficacy. GLV-1h99-mediated expression of the hNET protein in infected cells resulted in specific uptake of the radiotracer [131I]-meta-iodobenzylguanidine (MIBG). In mice, GLV-1h99-infected tumors were readily imaged by [124I]-MIBG positron emission tomography. To our knowledge, GLV-1h99 is the first oncolytic virus expressing the hNET protein that can efficiently eliminate tumors and simultaneously allow deep-tissue imaging of infected tumors.

A Haplotype of the Norepinephrine Transporter (Net) Gene Slc6a2 is Associated with Clinical Response to Atomoxetine in Attention-Deficit Hyperactivity Disorder (ADHD)

Atomoxetine is a specific inhibitor of the norepinephrine transporter (NET) that has demonstrated efficacy in the treatment of children with attention-deficit hyperactivity disorder (ADHD). We investigated whether polymorphisms in the NET/SLC6A2 gene may influence atomoxetine response in ADHD. Two independent cohorts of 160 and 105 ADHD children treated for 6 weeks with atomoxetine (0.5-1.8 mg/kg per day) were genotyped on CYP2D6, which metabolizes atomoxetine, and 108 single nucleotide polymorphisms in the NET/SLC6A2 gene. Response was defined as a minimum decrease of 25% in ADHD Rating Scale IV-Parent Version and a Clinical Global Impression-Severity (CGI-S) score less than or equal to 2 at week 6. Interindividual response was independent of the genetic variants of CYP2D6. Significant (p<0.05) associations between 20 NET/SLC6A2 single nucleotide polymorphisms (SNPs) and clinical efficacy in atomoxetine responders, compared with non-responders, were observed. The genomic region across exons 4 to 9 of NET/SLC6A2, where 36 SNPs have been genotyped, was associated with treatment response in both cohorts (p<0.01, odds ratio=2.2 and p=0.026, odds ratio=6.3, respectively), in the combined cohort (p<0.01, odds ratio=1.83), and in the subgroup of Caucasians only (p=0.02, odds ratio=1.8). Clinical efficacy of atomoxetine treatment in ADHD shows potential dependence upon a series of genetic polymorphisms of its mechanistic target, the norepinephrine transporter. Taking into account the high heritability of ADHD, the significance of the present finding and replication of a similar haplotype allele sequence result in an independent cohort, it is suggested that further assessment of this region could be useful in determining response to atomoxetine in ADHD.

Genetic predictors of response to antidepressants in the GENDEP project

The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P=0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.

Norepinephrine transport-mediated gene expression in noradrenergic neurogenesis

BackgroundWe have identified a differential gene expression profile in neural crest stem cells that is due to deletion of the norepinephrine transporter (NET) gene. NET is the target of psychotropic substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET mutations have been implicated in depression, anxiety, orthostatic intolerance and attention deficit hyperactivity disorder (ADHD). NET function in adult noradrenergic neurons of the peripheral and central nervous systems is to internalize norepinephrine from the synaptic cleft. By contrast, during embryogenesis norepinephrine (NE) transport promotes differentiation of neural crest stem cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors block noradrenergic differentiation. While the structure of NET und the regulation of NET function are well described, little is known about downstream target genes of norepinephrine (NE) transport.ResultsWe have prepared gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) mouse neural crest cells using long serial analysis of gene expression (LongSAGE). Comparison analyses have identified a number of important differentially expressed genes, including genes relevant to neural crest formation, noradrenergic neuron differentiation and the phenotype of NETKO mice. Examples of differentially expressed genes that affect noradrenergic cell differentiation include genes in the bone morphogenetic protein (BMP) signaling pathway, the Phox2b binding partner Tlx2, the ubiquitin ligase Praja2, and the inhibitor of Notch signaling, Numbl. Differentially expressed genes that are likely to contribute to the NETKO phenotype include dopamine-β-hydroxylase (Dbh), tyrosine hydroxylase (Th), the peptide transmitter 'cocaine and amphetamine regulated transcript' (Cart), and the serotonin receptor subunit Htr3a. Real-time PCR confirmed differential expression of key genes not only in neural crest cells, but also in the adult superior cervical ganglion and locus ceruleus. In addition to known genes we have identified novel differentially expressed genes and thus provide a valuable database for future studies.ConclusionLoss of NET function during embryonic development in the mouse deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic cell differentiation. The data further suggest deregulation of signaling pathways in the development and/or function of the NET-deficient peripheral, central and enteric nervous systems.

Human Sympathetic Nerve Biology

Patients with panic disorder provide a clinical model of stress. On a "good day," free from a panic attack, they show persistent stress-related changes in sympathetic nerve biology, including abnormal sympathetic nerve single-fiber firing ("salvos" of multiple firing within a cardiac cycle) and release of epinephrine as a cotransmitter. The coreleased epinephrine perhaps originates from in situ synthesis by phenylethanolamine N-methyltransferase (PNMT). In searching for biological evidence that essential hypertension is caused by mental stress--a disputed proposition--we note parallels with panic disorder, which provides an explicit clinical model of stress: (1) There is clinical comorbidity; panic disorder prevalence is increased threefold in essential hypertension. (2) For both, epinephrine cotransmission is present in sympathetic nerves. (3) In panic disorder and essential hypertension, but not in health, single-fiber sympathetic nerve firing salvos occur. (4) Tissue nerve growth factor is increased in both conditions (nerve growth factor is a stress reactant). (5) There is induction of PNMT in sympathetic nerves. Essential hypertension exhibits a further manifestation of mental stress: there is activation of noradrenergic brain stem neurons projecting to the hypothalamus and amygdala. These pathophysiological findings strongly support the view that chronic mental stress is important in the pathogenesis of essential hypertension. A hypothesis now under test is whether in both disorders, under prevailing conditions of ongoing stress, PNMT induced in sympathetic nerves acts as a DNA methylase, causing the norepinephrine transporter (NET) gene silencing that is present in both conditions. PNMT can have an intranuclear distribution, binding to DNA. We have demonstrated that the reduced neuronal noradrenaline reuptake present in both disorders does have an epigenetic mechanism, with demonstrable reduction in the abundance of the transporter protein, the NET gene silencing being associated with DNA binding by the methylation-related inhibitory transcription factor MeCP2.

Replication of a rare protective allele in the noradrenaline transporter gene and ADHD

Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families

Haplotype-tagging SNP analyses were conducted to identify molecular genetic substrates of quantitative phenotypes derived from performance on a Continuous Performance Task (CPT). Three hundred sixty-four individuals were sampled from 152 families ascertained on the basis of at least one child having ADHD. Probands, their affected and unaffected siblings, and parents were administered a CPT. Four different components of performance were analyzed and tested for association with SNPs from 10 candidate genes involved in monoaminergic function. After correcting for multiple comparisons and controlling for multiple individuals from the same family, significant associations were identified between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596), and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are excellent candidates as ADHD endophenotypes based on previously published criteria. Results also shed light on the molecular genetic basis of specific processes that may underlie the disorder.

Genome‐wide association study of response to methylphenidate in 187 children with attention‐deficit/hyperactivity disorder

We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N = 135) male) with mean age 9.2 +/- 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 and rs11134178; P = 3 x 10(-6)) fell short of the threshold for a genome-wide significant association. The most intriguing association among suggestive findings (rs3792452; P = 2.6 x 10(-5)) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P < or = 1 x 10(-2). These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate.

Interaction to personality between the serotonin transporter and norepinephrine transporter genes polymorphisms

Objective To assess the interaction to personality among 5-HTT LPR，5-HTT VNTR，NET T182C,NET G1287A.Methods 367 Han Chinese healthy people were assessed with EPQ personality include P,E，N latitude.Using PCR to detect gene polymorphism include 5-HTT and NET.Using SPSS13.0 and MDR to do statistical analysis.Results ①The distribution variance of the 5-HTT VNTR genetype and allele don't have statistical significance among different personality latitude(P＞0.05).②The mean T scores of N latitude's have statistical significance among L/S allele(t=2.232，P=0.026).③The mean T scores of E latitude's have statistical significance among T/C allele(t=2.680，P=0.008).④The distribution variance of G1287A genetype(X2=9.950.P=0.007)and allele(X2=9.644，P=0.002)have statistical significance between different grades in E latitude.The mean T scores of P latitude's have statistical significance among G/A allele(t=3.226,P=0.001).⑤There were no interaction among 5-HTT LPR，5-HTT VNTR，NET T182C，NET G1287A.Conclusions①There were no associations between the 5-HTT VNTR and EPQ personality latitude.②5-HTT LPR have associations with N latitude.L allele is the doubrful risk factor of neurotic personality.③NET T182C have associations with E latitude.T allele is the doubtful risk factor of introvert personality.④NETG1287A have associations with E and P latitude.G allele is the doubtful risk factor of introversion personality.A allele is the doubtful risk factor of psychoticism personality.⑤There were no interaction to personality among 5-HTT，NET genes polymorphisms. Key words: Serotonin transporter; Norepinephrine transporter; Gene polymorphism; EPQ personality

The combined effect of norepinephrine transporter gene and negative life events in major depression of Chinese Han population

The aim of the present study was to detect the combined effect of negative life events and the norepinephrine transporter (NET) gene on the development of major depression (MD) in a Chinese population. We recruited 388 unrelated patients affected with MD and 388 healthy controls in this study. The score of 32 was used as a cut-off value for grouping the negative life events into the severe and moderate forms using the Life Events Scale (LES). SNPs including rs2242446 and rs5569 of the NET gene were genotyped. The chi-square (chi (2)) test showed allelic association for the T-182C polymorphism (chi (2) = 6.46, corrected P = 0.011) and also showed genotypic association (chi (2) = 6.87, corrected P = 0.034). Multifactor dimensionality reduction (MDR) showed that the interaction between the rs2242446-rs5569 combination and negative life events had a CV consistency of 10 and PE of 0.3487. Compared with those having both T-G-MN combination used as reference group, we found that the OR scaled up from 1 to 7.39 (95%CI 3.40-16.06) in the C-A-SN group. The present study suggests that the combined effect of rs2242446 and rs5569 in the NET gene could modify the response to the negative life events in triggering MD.

No Evidence of an Association between Norepinephrine Transporter Gene Polymorphisms and Attention Deficit Hyperactivity Disorder

Neurobiological and pharmacological research has suggested that dysregulation of the central noradrenergic systems might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Previous studies have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 G1287A and –3081(A/T) polymorphisms with ADHD in Korean children and adolescents, and to determine the relationships of the genotypes of these two polymorphisms with continuous performance test results and the Junior Temperament and Character Inventory profiles of ADHD. In a case-control study, we assessed 186 ADHD probands and 150 normal controls; 109 trios were studied in a family-based association analysis. There were no significant differences in the genotype or allele frequencies of the SLC6A2 G1287A and –3081(A/T) polymorphisms between the ADHD and control groups (p > 0.05). In the transmission disequilibrium test analyses, there was no evidence for biased transmission of any of the alleles of the SLC6A2 G1287A and –3081(A/T) polymorphisms. In the haplotype analyses of these two polymorphisms, the global and individual χ² tests showed no significant associations between any of the haplotypes and ADHD. There were no significant differences with respect to the continuous performance test results and the Junior Temperament and Character Inventory profiles in the ADHD probands according to the genotypes of the SLC6A2 G1287A and –3081(A/T) polymorphisms. Our findings do not support SLC6A2 as a major genetic susceptibility factor in ADHD.

Pharmacogenetic study of atypical antipsychotic drug response: Involvement of the norepinephrine transporter gene

The identification of genetic factors underlying individual differences in antipsychotic drug response is of major interest. We investigated the involvement of two norepinephrine transporter gene polymorphisms in response to antipsychotics, comparing patients with strong and weak response to olanzapine and risperidone. We prospectively assessed short-term drug response in 75 Caucasian schizophrenic patients treated with these drugs, using the Positive and Negative Syndrome Scale. We then assessed the association between two SLC6A2 gene polymorphisms and drug response in this sample. No significant difference in genotype distribution was found between responders and non-responders, for the G1287A or T-182C polymorphism. The improvement in PANSS positive subscore was significantly greater in patients homozygous for the A1287 allele than in other patients, and significantly smaller in patients homozygous for the C-182 allele than in other patients. Our results suggest that these polymorphisms are specifically involved in the variation of positive symptoms in schizophrenic patients.

Combination of the serotonin transporter and norepinephrine transporter gene promoter polymorphisms might influence harm avoidance and novelty seeking in healthy females

It has been demonstrated that the interaction between serotonin transporter (5HTT) and norepinephrine transporter (NET) functions affects each transporter function and behavior in studies using knockout mice model. In the present study, we examined the effects of the 5HTT and NET gene promoter polymorphisms on personality traits in 575 Japanese healthy subjects. The 5HTT (long/short, L/S) and NET (-3081 A/T) genotypes were identified by PCR methods, and personality traits were assessed by the Temperament and Character Inventory (TCI). Neither of the two polymorphisms affected any TCI dimension, but the interaction between them had significant effects on harm avoidance and novelty seeking in females. Subsequent analyses showed that the females with the combination of the SS genotype reducing 5HTT function and the TT genotype reducing NET function had higher harm avoidance and lower novelty seeking. The present study suggests that the combination of 5HTT and NET polymorphisms influences harm avoidance and novelty seeking in females.