Positive Association between &lt;i&gt;T-182C&lt;/i&gt; Polymorphism in the Norepinephrine Transporter Gene and Susceptibility to Major Depressive Disorder in a Japanese Population

Inoue, Ken‐ichiro; Itoh, Ken; Yoshida, Keizo; Shimizu, Tetsuo; Suzuki, Toshio

doi:10.1159/000080957

Cited by 56 publications

(28 citation statements)

References 34 publications

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“…SLC6A2 gene encodes a transporter, which regulates norepinephrine (noradrenaline) homeostasis and the reuptake of norepinephrine into presynaptic nerve terminals. 24 SLC6A2 polymorphisms have been reported to be associated with depression 25,26 and response to antidepressants. 27,28 (v) SNPs or haplotypes in SLC6A3 (dopamine transporter or DAT1, located at 5p15.33), which encodes a transporter that is important in dopaminergic neurotransmission, were associated with risk for MDD or relative reduction of HAM-D21.…”

Section: Discussionmentioning

confidence: 99%

Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans

2009

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We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 (ABCB1), the noradrenaline, dopamine, and serotonin transporters (SLC6A2, SLC6A3 and SLC6A4), cyclic AMP-responsive element binding protein 1 (CREB1), corticotropin-releasing hormone receptor 1 (CRHR1) and neurotrophic tyrosine kinase type 2 receptor (NTRK2). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.00054±0.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2-coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and drug response. Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases.

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Section: Discussionmentioning

confidence: 99%

Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans

2009

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“…In previous studies, no association has been found between susceptibility to major depression and a non-synonymous (Owen et al, 1999) or five synonymous single nucleotide polymorphisms (Stöber et al, 1996) in the gene encoding the hNET. However, more recently, a positive association between a T182C polymorphism in the NET gene and susceptibility to major depressive disorder has been reported in a Japanese population (Inoue et al, 2004). Using brain tissues collected post mortem from patients diagnosed with major depression, Klimek et al (1997) have shown reduced expression of the NET (decreased [ 3 H]nisoxetine binding) in the locus coeruleus as compared to age-matched normal control subjects.…”

Section: Introductionmentioning

confidence: 99%

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Dziedzicka-Wasylewska

Faron-Górecka

Kuśmider

et al. 2006

Neuropsychopharmacol

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One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap. Many ADs increase synaptic NE availability by inhibition of the reuptake of NE. Using mice lacking NE transporter (NET À/À ) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles. In both tests, the NET À/À mice behaved like wild-type (WT) mice acutely treated with ADs. Autoradiographic studies showed decreased binding of the b-adrenergic ligand [ 3 H]CGP12177 in the cerebral cortex of NET À/À mice, indicating the changes at the level of b-adrenergic receptors similar to those obtained with ADs treatment. The binding of [ 3 H]prazosin to a 1 -adrenergic receptors in the cerebral cortex of NET À/À mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice. A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine. Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET À/À mice. In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET À/À mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test. From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.

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“…However, this was based on only 51 patients. [23][24][25][26] An important question is why so few candidate genes were replicated by our GWAS, whereas the sample size of our study was so much larger than any of the 78 selected candidate gene studies. One possible-and in our opinion most likely-explanation is publication bias; positive results have a better chance of being published than negative results.…”

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confidence: 99%

Poor replication of candidate genes for major depressive disorder using genome-wide association data

et al. 2010

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Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P = 0.038; odds ratio (OR) AT = 1.10, 95% CI 0.95-1.29; OR TT = 1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P = 0.034; OR C allele = 0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T = 1.35, 95% CI 1.13-1.63; P = 0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P = 0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

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Positive Association between <i>T-182C</i> Polymorphism in the Norepinephrine Transporter Gene and Susceptibility to Major Depressive Disorder in a Japanese Population

Cited by 56 publications

References 34 publications

Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans

Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Poor replication of candidate genes for major depressive disorder using genome-wide association data

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