unipolar depression negative association studies


Attention Valued Visitor: A Drug Reference Page for FDA Approved General Anesthetics is now available!
Shawn Thomas (Shawn@neurotransmitter.net) is working to summarize the mechanisms of action of every drug approved by the FDA for a brain- related condition. In addition, new pages with more automated content will soon replace some of the older pages on the web site. If you have suggestions about content that you would like to see, e-mail Shawn@neurotransmitter.net if you have anything at all to share.


Web www.neurotransmitter.net

(Updated 2/05/05)

Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ.
Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior.
Neuropsychobiology. 2003;48(4):186-9.
"Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, has been implicated in both mood disorders and suicidal behavior. This study has examined the association between the BDNF gene Val66Met polymorphism and mood disorders, age of onset and suicidal behavior in a Chinese sample population. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing depression groups (total, bipolar disorder or major depression) and control subjects. Furthermore, it was not demonstrated that this BDNF polymorphism was associated with age of onset or suicidal history in our mood disorder patients. Based on these results, it seems reasonable to suggest that this polymorphism is unlikely to play a major role in the genetic susceptibility to mood disorders. Given the fact that the positive association between BDNF gene Val66Met polymorphism and bipolar disorder has only been demonstrated for a Caucasian population but not for a Japanese analog or our Chinese sample, it appears likely that this association is ethnicity dependent." [Abstract]

Frisch A, Postilnick D, Rockah R, Michaelovsky E, Postilnick S, Birman E, Laor N, Rauchverger B, Kreinin A, Poyurovsky M, Schneidman M, Modai I, Weizman R.
Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways.
Mol Psychiatry 1999 Jul;4(4):389-92
"Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance of the genetic component is well accepted,2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects." [Abstract]

Khait VD, Huang YY, Zalsman G, Oquendo MA, Brent DA, Harkavy-Friedman JM, Mann JJ
Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects.
Neuropsychopharmacology. 2005 Jan;30(1):166-72.
Serotonin 5-HT2A receptor (5-HT2A) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive-impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive-impulsive traits has not been established. This study examines the possible association of the 5-HT2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT2A binding kinetics (Bmax and KD) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher Bmax in all subjects (F=3.53, df=2,211; p=0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F=7.56, df=2,60, p=0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. Bmax was not related to a diagnosis of mood disorders. The TT genotype appears associated with higher platelet 5-HT2A Bmax in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology. [Abstract]

Chotai J, Serretti A, Lorenzi C
Interaction between the Tryptophan Hydroxylase Gene and the Serotonin Transporter Gene in Schizophrenia but Not in Bipolar or Unipolar Affective Disorders.
Neuropsychobiology. 2004 Dec 20;51(1):3-9.
Increasing focus is being given to identify possible combinations of genes related to specific clinical phenotypes. In our sample of 814 patients comprising 114 with schizophrenia, 416 with bipolar affective disorder and 284 with unipolar affective disorder, we studied interactions between the tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR), and the dopamine receptor (DRD4) genes in relation to five major psychiatric symptomatology scores. There was significant interaction between the TPH and the 5-HTTLPR genes. With an increasing number of short (s) alleles of 5-HTTLPR, the scores for delusions, disorganization and negative symptoms were significantly decreasing among subjects having the TPH genotype AA but increasing among subjects having the TPH genotype AC, yielding the highest scores for the combinations AA x ll and AC x ss. Since high scores on just delusions, disorganization and negative symptoms but low scores on excitement and depression were found among subjects with schizophrenia, we conducted comparisons among the three diagnostic categories and controls as regards the combined TPH x 5-HTTLPR genotype distribution. Schizophrenia subjects had a significantly different distribution of the genotype combination for TPH x 5-HTTLPR as compared to 241 controls or to unipolar or bipolar subjects, and had significantly higher frequencies of AA x ll and of AC x ss. Thus, an interaction between TPH and 5-HTTLPR genes constitutes susceptibility to schizophrenia, thereby yielding apparent relationships between the major psychiatric symptomatology scores and genotype combinations in samples that are obtained by pooling schizophrenia with other diagnostic categories. Copyright (c) 2005 S. Karger AG, Basel. [Abstract]

Kunugi H, Vallada HP, Hoda F, Kirov G, Gill M, Aitchison KJ, Ball D, Arranz MJ, Murray RM, Collier DA.
No evidence for an association of affective disorders with high- or low-activity allele of catechol-o-methyltransferase gene.
Biol Psychiatry 1997 Aug 15;42(4):282-5
"Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample." [Abstract]

Serretti A, Cusin C, Cristina S, Lorenzi C, Lilli R, Lattuada E, Grieco G, Costa A, Santorelli F, Barale F, Smeraldi E, Nappi G.
Multicentre Italian family-based association study on tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.
Psychiatr Genet. 2003 Jun;13(2):121-6.
"OBJECTIVE: The aim of the present study was to investigate tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 genes in mood disorders using a family-based association approach. METHODS: The sample included 134 nuclear mood disorder families, with subjects affected by bipolar disorder (n=103) or major depressive disorder (n=58). All subjects were genotyped using polymerase chain reaction techniques. RESULTS: No significant transmission disequilibrium was found in the overall sample for any polymorphism. Analysis considering bipolar subjects only, or psychopathology traits as affection status did not influence the observed results. CONCLUSIONS: The study could not support the involvement of tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders." [Abstract]

Ohara K, Nagai M, Suzuki Y, Ohara K.
Low activity allele of catechol-o-methyltransferase gene and Japanese unipolar depression.
Neuroreport 1998 May 11;9(7):1305-8
"Several studies have shown that depressed patients have significantly lower catechol-o-methyltransferase (COMT) activity than healthy controls. Two COMT genes coding for low activity, COMTL, and high activity, COMTH have been identified. We undertook an association study on 75 depressive disorder patients, 40 bipolar disorder patients and 135 healthy controls. All the subjects were Japanese. Patients with depressive disorders exhibited a significantly higher rate of genotypes with the COMTL allele than healthy controls (p = 0.012), which was not the case in patients with bipolar disorders. The presence of the COMTL allele was significantly associated with depressive disorders (odds ratio 2.19, 95% CI 1.19-4.03). Our results suggest the COMTL allele contributed to the etiologies of depressive disorders." [Abstract]

Zill P, Baghai TC, Engel R, Zwanzger P, Schule C, Minov C, Behrens S, Bottlender R, Jager M, Rupprecht R, Moller HJ, Ackenheil M, Bondy B.
Beta-1-adrenergic receptor gene in major depression: influence on antidepressant treatment response.
Am J Med Genet. 2003 Jul 1;120B(1):85-9.
"Noradrenergic dysfunction has been implicated in the development of affective disorders. beta-adrenergic receptors (betaARs) mediate the response to norephinephrine, are coupled to the cAMP signaling cascade, supposed to be altered in their density and/or sensitivity in depression, and down regulated in several brain regions after long term treatment with different but not all antidepressants. A recently identified functional polymorphism in the beta(1)-adrenergic receptor (G1165C) leading to the amino acid variation Gly389Arg was associated with an enhanced coupling to the stimulatory G(s)-protein and increased adenylyl cyclase activation, disturbances which are often observed in affective disorders. Therefore, we investigated whether this beta(1)AR polymorphism is associated with major depression or with the response to antidepressant treatment in a sample of 259 patients compared to 206 healthy controls. Although we could not detect an association between the beta(1)AR polymorphism and major depression we found a tendency for a relation between CC homozygosity and a better and even faster response to antidepressant treatment in those patients, which were treated with antidepressants affecting directly or indirectly the beta(1)AR system (tricyclic antidepressants, noradrenergic and serotonergic specific agents, selective noradrenaline reuptake inhibitors) determined by the HAMD and CGI score (P = 0.05). However, after correction for multiple testing (Bonferroni) these results did not remain significant. Nevertheless, these findings suggest that the presence of the C allele might be an indicator for antidepressant treatment response." [Abstract]

Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS, Pyo CW, Han H.
Tumor necrosis factor-beta gene polymorphism may not be associated with major depressive disorder in the Korean population.
Psychiatry Clin Neurosci 2003 Feb;57(1):31-5
"Tumor necrosis factor (TNF)-beta has been implicated in the regulation of immune system. Alterations of the immune system in patients with major depressive disorder (MDD) have been also proposed to date. The present study was undertaken to investigate whether TNF-beta gene polymorphism is associated with MDD in the Korean population. Ninety-five patients with MDD who met the criteria of DSM-IV and 202 gender- and age-matched unrelated volunteers participated in the study. Genotyping for TNF-beta gene was performed by a polymerase chain reaction-restriction fragment length polymorphism method. The genotype and allele distribution in patients with MDD was similar to that of the controls. This study suggests that the TNF-beta gene polymorphism does not confer a susceptibility to MDD in the Korean population. A larger scaled study to examine different races is necessary to determine a role in the pathogenesis of MDD." [Abstract]

Blazer DG, Burchett BB, Fillenbaum GG.
APOE epsilon4 and low cholesterol as risks for depression in a biracial elderly community sample.
Am J Geriatr Psychiatry 2002 Sep-Oct;10(5):515-20
"OBJECTIVE: The epsilon4 allele of apolipoprotein (APOE) is known to be associated with a number of adverse health outcomes, yet the association of the allele with depression has not been conclusively determined. The authors explored the hypothesis that the epsilon4 allele is a risk factor for depression among older persons with a low cholesterol level (a known risk factor for depression). METHODS: A biracial community sample of 2,550 older African Americans and Whites in North Carolina was genotyped for APOE, tested for cholesterol, and evaluated for depression at both baseline and 4-year follow-up. RESULTS: No relationship was found between the epsilon4 allele and depression or low cholesterol and depression in either cross-sectional or longitudinal analyses. The interaction of the epsilon4 allele and cholesterol was also not associated with depression in controlled analyses. Female gender, less education, being unmarried, and cognitive impairment were associated with depression in cross-sectional controlled analyses; only cognitive impairment was associated with depression in longitudinal analyses. CONCLUSION: Despite the association of the epsilon4 allele with a number of adverse health outcomes, as well as the association between depression and cholesterol in previous studies, no association was found between epsilon4 and low cholesterol or depression in cross-sectional and longitudinal analyses. The interaction of epsilon4 and cholesterol was not associated with depression." [Abstract]

Hong CJ, Wang YC, Tsai SJ.
Association study of angiotensin I-converting enzyme polymorphism and symptomatology and antidepressant response in major depressive disorders.
J Neural Transm 2002 Sep;109(9):1209-14
"Angiotensin-converting enzyme (ACE) inhibitor has mood-elevating effects, and central ACE activity is increased for suicidal patients. In addition, substance P (SP), which is degraded by ACE, has been implicated in the pathogenesis of, and evaluated in the treatment for, major depressive disorder (MDD). The present study has tested the hypothesis that an ACE-gene insertion/deletion (I/D) polymorphism is associated with onset age, clinical manifestations, suicide history, and/or antidepressant response for two groups of MDD patients. No significant differences were demonstrated for onset age (p = 0.520), suicide history (p = 0.823), or baseline, total and cluster scores for Hamilton Depression Rating Scale comparing the three ACE genotypes. Further, previous findings that this ACE polymorphism is associated with therapeutic antidepressant effects were not replicated. The results demonstrate that these ACE variants did not play a major role in the clinical manifestations or antidepressant response for our MDD patients." [Abstract]

Segman RH, Shapira Y, Modai I, Hamdan A, Zislin J, Heresco-Levy U, Kanyas K, Hirschmann S, Karni O, Finkel B, Schlafman M, Lerner A, Shapira B, Macciardi F, Lerer B.
Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia.
Am J Med Genet 2002 Apr 8;114(3):310-4
"Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined." [Abstract]

Baghai TC, Schule C, Zwanzger P, Minov C, Zill P, Ella R, Eser D, Oezer S, Bondy B, Rupprecht R.
Hypothalamic-pituitary-adrenocortical axis dysregulation in patients with major depression is influenced by the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene.
Neurosci Lett 2002 Aug 16;328(3):299-303
"The Dex/CRH test is one of the most reliable neuroendocrine function tests for hypothalamic-pituitary-adrenocortical (HPA) system dysregulation in depression. Persistent overdrive of HPA system activity after successful antidepressant treatment predicts an enhanced risk for relapse of a depressive episode. As the renin-angiotensin system has been shown to play a role in HPA system activity, we investigated the impact of the angiotensin converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism, which determines ACE plasma concentrations, on HPA system dysregulation. We performed repeated combined Dex/CRH tests in 115 patients suffering from major depression. Dex/CRH test results were related to the I/D polymorphism within the ACE gene, which was assessed by PCR. Genotype frequencies were comparable to those in the general population (I/I 16.8%, I/D 59.3%, D/D 23.9%). D/D genotypes showed a higher cortisol stimulation during the first Dex/CRH test after admission than homozygous I-allele carriers (repeated measurement ANOVA: P=0.034). Cortisol area under the curve values were highest in those with the D/D genotype (mean+/-SEM [nmol/l*75 min]: 12700+/-2220), intermediate in those with the I/D genotype (9570+/-1000), and lowest in those with the I/I genotype (5160+/-1000; ANOVA: P=0.04). After successful antidepressive treatment and attenuation of HPA system overdrive these differences were no more detectable. The HPA axis stimulating properties of higher ACE and consecutively higher AT-II and/or lower substance P concentrations may be crucial factors for the HPA system hyperactivity during major depressive episodes." [Abstract]

Zill P, Baghai TC, Zwanzger P, Schule C, Minov C, Behrens S, Rupprecht R, Moller HJ, Engel R, Bondy B.
Association analysis of a polymorphism in the G-protein stimulatory alpha subunit in patients with major depression.
Am J Med Genet 2002 Jul 8;114(5):530-2
"Growing evidence suggests that G-proteins may be involved in pathogenesis and treatment of affective disorders. Several studies have reported altered levels and/or activities of stimulatory G-proteins in depression. The aim of this study was to investigate whether a polymorphism in the stimulatory alpha subunit of G-proteins (T/C point mutation in exon 5; ATT --> ATC at codon 131) is associated with major depression or response to antidepressant treatment. Therefore, we performed a case-control association study with 212 depressive patients and 137 healthy, unrelated controls. There was no evidence for an association between the investigated polymorphism in the G(alpha)(s) gene and major depression, as well as to treatment response. The results of our study are in concordance with recently published findings which do not support the hypothesis that the gene for the stimulatory alpha subunit of G-proteins is a major susceptibility factor in the pathophysiology of major depression." [Abstract]

Hattori E, Yamada K, Ebihara M, Toyota T, Nankai M, Shibuya H, Yoshikawa T.
Association study of the short tandem repeat in the 5' upstream region of the cholecystokinin gene with mood disorders in the Japanese population.
Am J Med Genet 2002 Jul 8;114(5):523-6
"We have recently identified a novel polymorphic short tandem repeat (STR) in the 5' upstream region of the cholecystokinin (CCK) gene and reported its association with panic disorder. A linkage study of affective disorder showed a modest linkage signal on the short arm of chromosome 3, the location of the CCK gene. Furthermore, clinical comorbidity of depression and anxiety disorders have been documented. In the present study, we examined a possible association of the CCK STR with mood disorders. We genotyped 165 subjects with mood disorders consisting of unipolar and bipolar disorders and 253 control samples. However, no significant allelic associations were detected between the STR and either the combined mood disorders (P = 0.885), the unipolar group (P = 0.296), or the bipolar group (P = 0.605). These data suggest that the CCK promoter STR is unlikely to have a major genetic effect on the development of mood disorders in the Japanese population." [Abstract]

Jahnes E, Muller DJ, Schulze TG, Windemuth C, Cichon S, Ohlraun S, Fangerau H, Held T, Maier W, Propping P, Nothen MM, Rietschel M.
Association study between two variants in the DOPA decarboxylase gene in bipolar and unipolar affective disorder.
Am J Med Genet 2002 Jul 8;114(5):519-22
"Irregularities of dopaminergic and serotonergic neurotransmission have been implicated in a variety of neuropsychiatric disorders. DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase, is an enzyme involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. Therefore, the DDC gene can be considered as a candidate gene for affective disorders. Recently, two novel variants were reported in the DDC gene: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Subsequently, an association case-control study including 112 English patients and 80 Danish patients with bipolar affective disorder (BPAD) revealed a significant association with the 1-bp deletion. This finding prompted us to analyze whether this effect was also present in a larger and ethnically homogeneous sample of 228 unrelated German patients with BPAD (208 patients with BP I disorder, 20 patients with BP II disorder), 183 unrelated patients with unipolar affective disorder (UPAD), and 234 healthy control subjects. For both BPAD and UPAD we could not detect a genetic association with either variant. Thus, our results do not support an involvement of the 1-bp or 4-bp deletion within the DDC gene in the etiology of affective disorders." [Abstract]

Serretti A, Cristina S, Lilli R, Cusin C, Lattuada E, Lorenzi C, Corradi B, Grieco G, Costa A, Santorelli F, Barale F, Nappi G, Smeraldi E.
Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders.
Am J Med Genet 2002 May 8;114(4):361-9
"Variants of the functional polymorphism in the serotonin transporter (upstream regulatory region: 5-HTTLPR), the tryptophan hydroxylase (TPH), the monoamine oxidase A (MAO-A), and the dopamine receptor D4 (DRD4) genes have all been associated with mood disorders. The aim of this study was to test those hypotheses by using a family-based association approach. Both diagnoses and psychopathology were used for phenotype definitions. A total of 134 nuclear families with mood disorders, with probands affected by bipolar (n = 103) or major depressive (n = 58) disorders, were included in the study. All subjects were typed for the above-mentioned gene variants using polymerase chain reaction (PCR) technique. No significant transmission disequilibrium was found in the overall sample for any polymorphism. A separate analysis of bipolar subjects only, or the use of continuous psychopathologic traits as affectation status did not influence the observed results. Our study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders." [Abstract]

Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS, Han H.
Report on IL-10 gene polymorphism at position -819 for major depression and schizophrenia in Korean population.
Psychiatry Clin Neurosci 2002 Apr;56(2):177-80
"The present study was carried out to examine the relationship of interleukin (IL)-10 gene polymorphism at position -819 for major depression and schizophrenia in the Korean population. DNA was extracted from 92 Korean patients with major depression, 141 Korean patients with schizophrenia, and 146 ethnically matched controls. DNA was amplified by a polymerase chain reaction-based method and digested by MaeIII, and the restriction fragment length polymorphism of two alleles, IL-10*C and IL-10*T, were assessed. There were no significant differences in genotype frequencies of IL-10*T/T, IL-10*T/C, and IL-10*C/C as well as allelic frequencies of IL-10*T and IL-10*C between patients with major depression and controls in the Korean population. Comparison of genotype and allelic frequencies of IL-10 gene between patients with schizophrenia and controls were also not significant. The present study suggests that IL-10 gene polymorphism at position -819 does not confer susceptibility to major depression and schizophrenia, at least in the Korean population. Further systematic studies including various clinical variables would be required." [Abstract]

Zill P, Engel R, Baghai TC, Juckel G, Frodl T, Muller-Siecheneder F, Zwanzger P, Schule C, Minov C, Behrens S, Rupprecht R, Hegerl U, Moller HJ, Bondy B.
Identification of a naturally occurring polymorphism in the promoter region of the norepinephrine transporter and analysis in major depression.
Neuropsychopharmacology 2002 Apr;26(4):489-93
"Disturbances in the noradrenergic neurotransmission system have been implicated in the etiology of mood disorders. The norepinephrine transporter (NET) is a main target of antidepressant action and was shown to be dysregulated in major depression. Despite the clinical and physiological significance of NET gene regulation, little is known about the transcriptional control mechanisms governing its expression. Since it is well established that affective disorders have a genetic component with many genes of small effect contributing to the genetic susceptibility of depression, the NET gene is an interesting candidate gene for affective disorders. In a search for polymorphisms or mutations in the 5' flanging region of the NET gene we sequenced approximately 1000 bp upstream of the first codon in the NET gene promoter in 100 patients with major depression and 100 healthy controls. We identified a so far unknown T --> C polymorphism 182 bp upstream of the start codon in a transcriptional relevant region. In a case control association study we investigated the newly identified T-182C polymorphism and an already known G1287A polymorphism in exon 9 of the NET gene in a sample of 193 patients with major depression and 136 healthy, non-related controls. No statistical significant differences between patients and controls were found for any of the analyzed polymorphisms, either in the genotype distribution or in the allele frequencies. Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of major depression." [Abstract]

Owen D, Du L, Bakish D, Lapierre YD, Hrdina PD.
Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression.
Psychiatry Res 1999 Jul 30;87(1):1-5
"The monoamine neurotransmitters serotonin, norepinephrine and dopamine have been implicated in the pathogenesis of depression, schizophrenia and mood disorders. The mechanism of action of certain antidepressant drugs, particularly the tricyclics and the newly available norepinephrine and serotonin reuptake inhibitors (NSRIs) drugs, venlafaxine and nefazodone, suggest that the norepinephrine transporter, which is a target for these antidepressant drugs, and its malfunction may be involved in major depression. In this association study, we tested the hypothesis that variants of the human norepinephrine transporter (NET) gene confer susceptibility to major depression. One hundred and five patients with major depression and 74 unrelated matched controls were analyzed for a silent 1287G/A polymorphism (NET-8) in exon 9 of the NET gene. No significant differences in genotype or allele frequencies were found between controls and patients, nor between subgroups of depressed patients classified by suicidal ideation. In addition, 60 controls and 60 patients were genotyped for a missense substitution Thr99Ile in exon 2 of the NET gene (NET-1), but only one control was heterozygous for this variant. These results suggest that the NET gene is unlikely to be involved in the susceptibility to major depression." [Abstract]

Zill P, Engel R, Baghai TC, Zwanzger P, Schule C, Minov C, Behrens S, Rupprecht R, Moller HJ, Bondy B.
Analysis of polymorphisms in the olfactory G-protein Golf in major depression.
Psychiatr Genet 2002 Mar;12(1):17-22
"It is well established that G-proteins represent essential regulatory components in transmembrane signaling. The alpha subunit of the olfactory G-protein Golf (GNAL) maps to a region on chromosome 18 where linkage to affective disorders has been reported, as well as a parent-of-origin effect in affective disorders with some markers near the locus for the alpha subunit of the Golf gene. We investigated whether two polymorphisms in the alpha subunit of the Golf gene (A-->G in intron 3, and T-->G in intron 10) are associated with major depression in 176 major depressive patients compared with 145 healthy control subjects, and additionally tested for a parent-of-origin effect in separated gender groups. In the control group, we found a significant increase in the G-allele frequency of the intron 3 polymorphism in females (P=0.0036, odds ratio=2.13, 95% confidence interval=1.29-3.54, Fisher's Exact Test). In patients, we found a similar tendency for higher G-allele frequencies in females. Concerning the intron 10 polymorphism, no differences in the genotype or allele frequencies were detectable for any of the separated gender groups. Also, the total patient and control groups showed no differences in allele or genotype frequencies for any of the investigated polymorphisms. The results of this study agree with the reported parent-of-origin effects on chromosome 18, but do not support the hypothesis that the Golf gene is a major susceptibility factor for major depression." [Abstract]

Yu YW, Chen TJ, Wang YC, Liou YJ, Hong CJ, Tsai SJ.
Association analysis for neuronal nitric oxide synthase gene polymorphism with major depression and fluoxetine response.
Neuropsychobiology. 2003;47(3):137-40.
"Nitric oxide (NO) is produced from its precursor L-arginine by the enzyme NO synthase (NOS), which includes at least three distinct isoforms - neuronal (nNOS), endothelial, and inducible NOS. Recent studies have implicated NOS in the mechanism that underlies the therapeutic efficacy of antidepressant medication. In addition, major depressive disorder (MDD) patients were found to have significantly higher plasma nitrate concentrations than normal subjects, an index of NO production, in comparison to normal subjects. In a population-based association study, we tested the hypothesis that the nNOS C276T polymorphism confers susceptibility to MDD. We also examined the association between this polymorphism and therapeutic fluoxetine response in 114 MDD patients who underwent a 4-week fluoxetine treatment. The results demonstrate that the nNOS variants are found at similar frequencies in MDD patients and healthy control subjects. Further, we did not discover any genetic variants that influenced the fluoxetine response in MDD patients treated with fluoxetine. Our findings suggest that this nNOS C276T polymorphism does not play a major role in the susceptibility to, or fluoxetine response in, MDD. However, the association between other NOS variants and MDD or antidepressant response, including sexual dysfunction, may warrant further investigation." [Abstract]

Adams JH, Wigg KG, King N, Burcescu I, Vetró A, Kiss E, Baji I, George CJ, Kennedy JL, Kovacs M, Barr CL
Association study of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and childhood-onset mood disorders.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):90-5.
Childhood-onset mood disorders (COMD) are often familial, and twin studies of COMD provide compelling evidence that genetic factors are involved. Deficits in neural plasticity have been suggested to underlie the development of depression. The receptor tropomyosin related kinase B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF), play essential roles in neural plasticity, and mRNA expression of both of these genes has been shown to be influenced by stress and chronic antidepressant treatment. In addition, TrkB knock-out mice display inappropriate stress coping mechanisms. Having previously shown that BDNF is associated with COMD, in this study we investigated the gene encoding TrkB, neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) as a susceptibility factor in COMD. We tested for association of NTRK2 with COMD in two independent samples: (a) a case-control sample matched on ethnicity and gender, consisting of 120 cases who met DSM III/IV criteria for major depressive or dysthymic disorder before age 14 or bipolar I/II before the age of 18, and controls, and (b) a family based control sample of 113 families collected in Hungary, identified by a proband between the age of 7 and 14 who met DSM IV criteria for major depressive disorder or bipolar I/II disorder. There was no evidence for an allelic or genotypic association of three polymorphisms of NTRK2 with COMD in the case-control sample. Also, in the family based sample, using the transmission disequilibrium test (TDT), we did not identify any evidence of allelic association for each marker individually or when haplotypes were analyzed. Based on these results, using these three polymorphisms, we do not find support for NTRK2 as a susceptibility gene for COMD. (c) 2004 Wiley-Liss, Inc. [Abstract]

Zill P, Baghai TC, Engel R, Zwanzger P, Schüle C, Eser D, Behrens S, Rupprecht R, Möller HJ, Ackenheil M, Bondy B
The dysbindin gene in major depression: an association study.
Am J Med Genet. 2004 Aug 15;129B(1):55-8.
The pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin-associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24-41]; Brambilla et al. [2003: Mol Psychiatry 8:721-737]]. Therefore, we investigated whether five SNPs in the dysbindin gene could be susceptibility factors in the ethiology of major depression or for the response to antidepressant treatment in a sample of 293 patients compared to 220 healthy controls. Applying single SNP evaluation, as well as haplotype analysis we could not detect an association between the dysbindin polymorphisms and major depression or the response to antidepressant treatment. In conclusion, our results suggest that SNPs in the dysbindin gene are unlikely to play a major role in the pathophysiology of major depression or are in linkage disequilibrium (LD) with a neighboring mutation or gene. Further analysis are needed to confirm these results. [Abstract]

Villafuerte SM, Del-Favero J, Adolfsson R, Souery D, Massat I, Mendlewicz J, Van Broeckhoven C, Claes S.
Gene-based SNP genetic association study of the corticotropin-releasing hormone receptor-2 (CRHR2) in major depression.
Am J Med Genet 2002 Mar 8;114(2):222-6
"An increasing amount of data suggests that affective disorders are related to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the stress-response system. Corticotropin-releasing hormone receptor-2 (CRHR2)-deficient mice display a stress-sensitive and anxiety-like phenotype suggesting that the CRHR2 is a plausible functional candidate gene influencing the reactivity of the HPA axis and therefore the liability to develop affective disorders. In this study, a gene-based single nucleotide polymorphism (SNP) map of the corticotropin-releasing hormone receptor 2 (CRHR2) was constructed containing one synonymous cSNP in exon 10, two intronic SNPs, and two SNPs in the 5' upstream regulatory region. No significant difference in allele or genotype frequency was found for four out of the five SNPs between Belgian unipolar (UP) patients and age-, gender-, and ethnicity-matched controls. The cSNP did show allelic and genotypic association with borderline significance (P=0.04). However, a replication study of this cSNP in a bipolar sample of Belgian origin and a Swedish UP sample did not show significant differences in allele and genotype frequencies." [Abstract]

Rujescu D, Giegling I, Sato T, Moeller HJ.
A polymorphism in the promoter of the serotonin transporter gene is not associated with suicidal behavior.
Psychiatr Genet 2001 Sep;11(3):169-72
"A 44 base pair deletion/insertion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was examined in 124 German suicide attempters, who were consecutively hospitalized, and 185 German normal control subjects without a history of any DSM-IV axis I or II mental disorder. Both patients and control subjects were recruited from the same geographic area. There was no significant difference in allele or genotype frequency between patients and control subjects. There were also no differences when the patients were divided into several subgroups (suicide attempters with a violent method, and suicide attempters with a lifetime history of mood disorders, unipolar depression, personality disorders). These results suggest that the 5-HTTLPR polymorphism is unlikely to play a major role in the genetic susceptibility to suicide attempts. Conflicting results among the present and previous studies regarding an association between the polymorphism and suicidal behavior, however, suggest the possibility that there may be unidentified specific subtypes of suicidal behavior that are significantly associated with the polymorphism or, alternatively, simply reflect false-positive association results." [Abstract]

Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS.
Polymorphism of CTLA-4 gene for major depression in the Korean population.
Psychiatry Clin Neurosci 2001 Oct;55(5):533-7
"This study was carried out to verify the relationship between major depression and cytotoxic T lymphocyte antigen-4 (CTLA-4), which is related to immunological function such as T-cell regulation. Among the Korean patients diagnosed with major depression according to DSM-IV, 77 patients without neurological illness, hormonal disorder, or comorbid mental illness were selected. The stored data on 149 normal Koreans from the Catholic Hemopoietic Stem Cell Bank of Korea, were used as a control group. The data of the Korean control group were compared with those of the studies of different ethnic groups. DNA was extracted from whole blood using proteinase K and the exon 1 region of CTLA-4 gene was amplified by polymerase chain reaction. Gene typing was performed using single strand conformation polymorphism. The results were assessed. There were significant differences in frequencies of CTLA-4 allele (chi2 = 56.472, d.f. = 1, P = 0.001) and genotype (chi2 = 46.132, d.f. = 2, P = 0.001) between the Korean population and the Caucasian population. However, we could not find any differences between the Korean and the Japanese population. There were no significant differences in genotype frequencies of CTLA-4*G/G, CTLA-4*G/A, and CTLA-4*A/A between the patients with major depression and the control group in the Korean population (48.1% vs. 46.3%, 41.6% vs 39.6%, 10.3% vs. 14.1%, respectively). There were no significant differences in allelic frequencies of CTLA-4*G and CTLA-4*A between the patients with major depression and the control group in the Korean population (68.8% vs. 66.1%, 31.2% vs. 33.9%, respectively). Although the present study produced negative results for the association of exon 1 polymorphism of CTLA-4 gene with major depression in the Korean population, further systematic research, including diverse clinical variables, would be necessary." [Abstract]

Lai IC, Hong CJ, Tsai SJ.
Association study of nicotinic-receptor variants and major depressive disorder.
J Affect Disord 2001 Sep;66(1):79-82
"BACKGROUND: Depressive patients are more likely to smoke than the general population and nicotine was found to reduce the incidence and severity of depressive symptoms in many studies. These findings suggest that nicotinic acetylcholine receptors (nAChRs) may be implicated in major depressive disorder. We tested the hypothesis that the allelic variant, 2 bp deletion, of the partially duplicated alpha7 nAChR gene confers susceptibility to major depressive disorder. METHODS: We genotyped alpha7 nAChR in 72 patients with major depressive disorder and 103 normal controls. Results: The distribution of the partially duplicated alpha7 nAChR genotypes (P=0.027) and alleles (P=0.037) suggests a modest difference between depressive patients and controls. LIMITATIONS: The -2 bp allele is thought to be present only in the duplicated exon 6, and the impact of the partially duplicated alpha7 nAChR and its -2 bp variant remain to be determined. CONCLUSIONS: The -2 bp allele of partially duplicated alpha7 nAChR may have an influence on the risk for development of major depressive disorder. The levels of significance achieved are modest and the findings must be replicated in other studies." [Abstract]

Syagailo YV, Stober G, Grassle M, Reimer E, Knapp M, Jungkunz G, Okladnova O, Meyer J, Lesch KP.
Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders.
Am J Med Genet 2001 Mar 8;105(2):168-71
"Functional characterization studies revealed that transcriptional activity of the human monoamine oxidase A (MAOA) gene is modulated by a polymorphic repetitive sequence located approximately 1.2 kb upstream of the ATG codon. To investigate the possible influence of the allelic variants of the MAOA gene-linked polymorphic region (MAOA-LPR) on the genetic predisposition to psychiatric disorders, we have performed a case-control association study. 174 patients with affective disorders and 258 patients with schizophrenia according to DSM-IV, as well as 229 population controls were tested. Statistical analysis showed no significant differences in allele or genotype frequencies between control and patient groups. Our results suggest that there is no association between MAOA-LPR genotype and susceptibility to recurrent major depression, bipolar disorder, and schizophrenia in our population." [Abstract]

Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Moller HJ, Dahmen N.
Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression.
Am J Med Genet. 2003 Feb 15;117B(1):1-6.
"This study was conducted to detect a possible association of a T941G single nucleotide polymorphism (SNP) in the monoamine oxidase A (MAOA) gene with generalized anxiety disorder (GAD), panic disorder (PD), or major depression (MD). Fifty GAD patients (34 females and 16 males), 38 PD patients (21 females and 17 males), and 108 MD patients (80 females and 28 males) were included. The comparison group consisted of 276 (132 females and 144 males) unrelated healthy individuals. The 941T allele was over-represented in patients suffering from GAD (chi(2) = 6.757; df = 1; P < 0.01, not corrected for multiple testing) when compared to healthy volunteers. No association was observed in MD or PD. This is the first study specifically analyzing the MAOA G941T polymorphism in GAD and thus needs to be replicated in an independent sample. However, the results are in line with previous data suggesting an association between the MAOA locus and regulation of complex human behavior." [Abstract]

Pauls J, Bandelow B, Ruther E, Kornhuber J.
Polymorphism of the gene of angiotensin converting enzyme: lack of association with mood disorder.
J Neural Transm 2000;107(11):1361-6
"The insertion/deletion polymorphism of the gene of angiotensin-converting enzyme (ACE) was investigated in a case-control study including 169 patients with suffering from either bipolar disorder type I or unipolar recurrent major depression (DSM-IV) and 169 healthy controls. No significant association was found with bipolar disorder type I or unipolar recurrent depression and the polymorphism of the ACE gene. A previously reported genetic association (Arinami et al., 1996) was not confirmed by the present study." [Abstract]

Furlong RA, Keramatipour M, Ho LW, Rubinsztein JS, Michael A, Walsh C, Paykel ES, Rubinsztein DC.
No association of an insertion/deletion polymorphism in the angiotensin I converting enzyme gene with bipolar or unipolar affective disorders.
Am J Med Genet 2000 Dec 4;96(6):733-5
"A recent Japanese study on the angiotensin I converting enzyme gene (ACE) insertion/deletion polymorphism reported that both the D allele (P < 0.02) and the DD genotype (P < 0.002) were significantly more frequent in affective disorder cases than in controls [Arinami et al., 1996: Biol Psychiatry 40:1122-1127]. A replication study was performed by using 157 bipolar I affective disorder cases, 169 major depressive disorder cases, and 313 controls. No significant association with this polymorphism was found in either disorder or in a combined affective disorder group. These results do not support the ACE gene having a major role in the etiology of either bipolar or unipolar affective disorders." [Abstract]

Toyota T, Watanabe A, Shibuya H, Nankai M, Hattori E, Yamada K, Kurumaji A, Karkera JD, Detera-Wadleigh SD, Yoshikawa T.
Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler.
Mol Psychiatry 2000 Sep;5(5):461, 489-94
"We introduced a new genotyping method, fluorescence resonance energy transfer-based melting curve analysis on the LightCycler, for the analysis of the gene, DUSP6 (dual specificity MAP kinase phosphatase 6), in affective disorder patients. The DUSP6 gene is located on chromosome 12q22-23, which overlaps one of the reported bipolar disorder susceptibility loci. Because of its role in intracellular signalling pathways, the gene may be involved in the pathogenesis of affective disorders not only on the basis of its position but also of its function. We performed association analysis using a T>G polymorphism that gives rise to a missense mutation (Leu114Val). No evidence for a significant disease-causing effect was found in Japanese unipolars (n = 132) and bipolars (n = 122), when compared with controls (n = 299). More importantly, this study demonstrates that melting curve analysis on the LightCycler is an accurate, rapid and robust method for discriminating genotypes from biallelic markers. This strategy has the potential for use in high throughput scanning for and genotyping of single nucleotide polymorphisms (SNPs)." [Abstract]

Desan PH, Oren DA, Malison R, Price LH, Rosenbaum J, Smoller J, Charney DS, Gelernter J.
Genetic polymorphism at the CLOCK gene locus and major depression.
Am J Med Genet 2000 Jun 12;96(3):418-21
"Genetic analysis in both mouse and Drosophila has indicated that the product of the CLOCK gene is an essential component of a circadian rhythm timing system. A single nucleotide polymorphism (SNP), T3111C, in the 3' flanking region of the human CLOCK gene has been identified. Homozygotes or heterozygotes for the 3111C allele have been reported to have higher mean scores on a measure of evening preference for activity (vs. morning preference) than subjects homozygous for the 3111T allele. Since major depression is hypothesized to be closely linked to circadian rhythms, we explored whether this polymorphism might be related to susceptibility to major depression. We also ascertained allele frequency in an African-American control population, to begin to evaluate population variation at this locus. CLOCK T3111C allele frequencies were determined in 280 European American (EA) subjects, 143 with a history of major depression and 137 screened controls, and in 58 African American (AA) screened control subjects, using a polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) method. There was no significant difference between EA depressed and control subjects in allele frequency. There was a significant difference in allele frequency between EA and AA subjects, demonstrating a potential for population stratification. In none of these groups were significant deviations from Hardy-Weinberg equilibrium found. The present data do not support an association between CLOCK gene alleles at the T3111C locus and major depression." [Abstract]

Bailer U, Wiesegger G, Leisch F, Fuchs K, Leitner I, Letmaier M, Konstantinidis A, Stastny J, Sieghart W, Hornik K, Mitterauer B, Kasper S, Aschauer HN
No association of clock gene T3111C polymorphism and affective disorders.
Eur Neuropsychopharmacol. 2005 Jan;15(1):51-5.
CLOCK was hypothesised to be related to susceptibility of affective disorders. To test subsamples of affectively disordered patients, we examined age of onset (AoO), numbers of episodes and melancholic type of clinical manifestation. Using PCR and RFLP, we investigated in patients with unipolar depression and bipolar disorder (BP) whether the CLOCK T3111C SNP is associated with affective disorders (n=102) compared to healthy controls (n=103). No differences were found either in genotype or allele frequency distributions of T3111C polymorphism between patients compared to healthy controls (p&gt;0.2). No deviations from Hardy-Weinberg Equilibrium (HWE) were detected either in patients, or healthy controls. Results suggest that there is no association between the T3111C SNP and affective disorders in general. Data of our sample replicate prior findings of Desan et al. [Am. J. Med. Genet. 12 (2000) 418]. Subsamples of patients with high numbers of affective episodes did show some deviations in genotypes (p=0.0585). [Abstract]

Hong CJ, Tsai SJ, Cheng CY, Liao WY, Song HL, Lai HC.
Association analysis of the 5-HT(6) receptor polymorphism (C267T) in mood disorders.
Am J Med Genet 1999 Dec 15;88(6):601-2
"The serotonergic system is implicated in the etiology of mood disorders. Among those most recently discovered serotonin receptors, the relative abundance of serotonin type 6 receptor (5-HT(6)) in the limbic area and the high affinity of some antidepressants to 5-HT(6) receptors suggest that this receptor might be involved in the pathogenesis of mood disorders. In a population-based association study, we tested the hypothesis that the allelic variant (C267T) of the human 5-HT(6) gene confers susceptibility to mood disorders. We genotyped the 5-HT(6) receptor in 139 patients with mood disorders and 147 controls. The results demonstrated that there were no significant differences in genotype or allele frequencies between controls and all patients, or between controls and patients with bipolar disorders or major depression, separately." [Abstract]

Huang YY, Grailhe R, Arango V, Hen R, Mann JJ.
Relationship of psychopathology to the human serotonin1B genotype and receptor binding kinetics in postmortem brain tissue.
Neuropsychopharmacology 1999 Aug;21(2):238-46
"Knockout of the 5-HT1B gene in mice results in increased aggression, as well as alcohol and cocaine consumption. Given the clinical association of aggression, suicide, alcoholism, and substance abuse, we studied relationship of psychopathology to the human 5-HT1B receptor gene (N = 178) and postmortem human 5-HT1B receptor binding (N = 96) in the brain. The sample comprised: 71 suicide victims, 107 nonsuicides, 45 with a history of major depression and 79 without, 64 with a history of a alcoholism or substance abuse and 60 without, as well as 36 with a history of pathological aggression and 42 without. Single-strand conformational polymorphism (SSCP) analysis and DNA sequencing techniques were used to screen the coding region of the human 5-HT1B receptor gene in genomic DNA isolated from postmortem human brain tissue. Two common polymorphisms were identified in the 5-HT1B receptor gene, involving a silent C to T substitution at nucleotide 129 and a silent G to C substitution at nucleotide 861 of the coding region. These polymorphisms were found with the same frequency in the suicide and the nonsuicide groups and in those with and without a history of major depression, alcoholism, or pathological aggression. The binding indices (Bmax and KD of the 5-HT1B receptor in prefrontal cortex also did not differ in suicides and controls, major depression, alcoholism, and cases with a history of pathological aggression. The C129 or G861 allele had 20% fewer 5-HT1B receptor compared to the 129T or 861C allele. We did not identify a relationship between suicide, major depression, alcoholism, or pathological aggression with 5-HT1B receptor binding indices or genotype." [Abstract]

Serretti A, Macciardi F, Cusin C, Lattuada E, Lilli R, Di Bella D, Catalano M, Smeraldi E.
GABAA alpha-1 subunit gene not associated with depressive symptomatology in mood disorders.
Psychiatr Genet 1998 Winter;8(4):251-4
"Considerable evidence implicates the neurotransmitter gamma-aminobutyric acid (GABA) in the biochemical pathophysiology of mood disorders. In this study, we investigated the possibility that the gene for the gamma-aminobutyric acid type A (GABAA) receptor alpha-1 subunit (GABRA1) might be associated with depressive symptomatology in a sample of mood disorder subjects. Sixty-seven inpatients affected by unipolar (n = 37) and bipolar (n = 30) disorder (DSMIV) were assessed at admission by the Hamilton depression rating scale (HAMD) and were typed using polymerase chain reaction (PCR) techniques. GABRA1 variants were not associated with depressive symptomatology, and consideration of possible stratification effects such as sex, psychiatric diagnosis and illness severity did not reveal any association either. GABAA alpha-1 subunit gene is not, therefore, associated with depressive symptomatology in mood disorder subjects." [Abstract]

Lappalainen J, Sanacora G, Kranzler HR, Malison R, Hibbard ES, Price LH, Krystal J, Gelernter J.
Mutation screen of the glutamate decarboxylase-67 gene and haplotype association to unipolar depression.
Am J Med Genet. 2004 Jan 1;124B(1):81-6.
"Abnormally low concentrations of brain gamma-aminobutyric acid (GABA) have been reported in unipolar depression. Almost all of the brain GABA is synthesized by glutamate decarboxylase (GAD) enzymes (GAD67 and GAD65). These enzymes, therefore, play a central role in brain GABA homeostasis. We screened all the 17 exons of the GAD67 gene for mutations using single strand conformation polymorphism (SSCP) or denaturing high pressure liquid chromatography (dHPLC) in a sample of 43 individuals diagnosed with major unipolar depression or other disorders with putative GABAergic dysfunction. We identified eight novel variants (five synonymous base substitutions, two insertion/deletions and one tandem repeat). Three relatively common (minor allele frequency >20%) single nucleotide polymorphisms (SNPs), located in the 5' non-coding region (exon 0), intron 8, and the 3' non-coding region (exon 16) of the gene, were genotyped in 103 European-American (EA) subjects with depression and 125 EA psychiatrically screened controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated using the 3LOCUS program. Significant LD was observed between the intron 8 SNP and the exon 16 SNP and between the exon 0 SNP and the exon 16 SNP. Three common GAD67 haplotypes were observed in this population, which accounted for >90% of the possible GAD67 three-locus haplotypes. Comparison of SNP and haplotype frequencies between individuals with depression and controls revealed no differences. These results demonstrate a significant within-gene LD for GAD67 in the EA population and begin to establish a haplotype map for this gene. Furthermore, these results suggest that common genetic variation within the GAD67 gene does not play a major role in the predisposition to unipolar depression." [Abstract]

Cervilla J, Prince M, Joels S, Russ C, Lovestone S.
Genes related to vascular disease (APOE, VLDL-R, DCP-1) and other vascular factors in late-life depression.
Am J Geriatr Psychiatry. 2004 Mar-Apr;12(2):202-10.
"OBJECTIVE: The authors asked whether polymorphic variation at three genes related to vascular disease, and other vascular disease risk factors, determine late-life depression. METHODS: A group of 370 participants, representing 57% of survivors of an initial cohort of 1,083 participants in the Medical Research Council treatment trial of hypertension in older adults, had been screened for depression at baseline and were traced and genotyped for genetic analysis 11 years later. Genetic analyses were performed to establish variability at three polymorphisms related to vascular disease: APOE encoding for apolipoprotein-E, VLDL-R encoding for the VLDL cholesterol-receptor, and DCP-1 encoding for angiotensin-converter enzyme. Information on vascular disease and its risk factors (ECG ischemia or arrhythmia, body mass index, serum cholesterol, smoking status, and systolic/diastolic blood pressure) and cognitive functioning was also available from baseline. RESULTS: The authors found no association between the three studied polymorphisms and depression. Female gender, higher diastolic blood pressure, poorer cognitive functioning, and smoking status at baseline were all associated with depression independently of antidepressant and NSAIDs use, age, ECG-established vascular disease, and the remaining vascular disease risk factors studied. CONCLUSIONS: This study found no association between late-life depression and three polymorphisms related to vascular disease. Depression was found to independently associated with smoking, female gender, poorer cognitive functioning, and higher diastolic blood pressure. Taken together, this study does not seem to support the notion of a specific link between the studied vascular risk factors or these vascular-related loci and late-life depression." [Abstract]

Kunugi H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T, Hirose T, Nanko S.
C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses.
Mol Psychiatry 1998 Sep;3(5):435-7
"A common missense mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been shown to be a risk factor for premature cardiovascular disease and neural tube defect. Deficient activity of MTHFR has also been implicated in the pathogenesis of psychiatric conditions such as schizophrenia and affective disorders. Arinami et al found an increased frequency of homozygosity for the mutated type (T677) of the MTHFR gene in schizophrenia and depression. We tried to replicate this finding in a sample of 343 patients with schizophrenia, 143 with bipolar disorder, 71 with unipolar depression, and 258 controls; however, there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls. Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample." [Abstract]

Furlong RA, Coleman TA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC.
No association of a functional polymorphism in the dopamine D2 receptor promoter region with bipolar or unipolar affective disorders.
Am J Med Genet 1998 Sep 7;81(5):385-7
"The dopaminergic system, along with the serotonergic and noradrenergic systems, has been implicated in the etiology of mood disorders. An association study of a functional variant in the promoter region of the dopamine D2 receptor (DRD2) with bipolar affective disorder I or unipolar major affective disorders was performed. Variable expression of the DRD2 gene in vitro has been shown with this promoter polymorphism. One hundred and thirty-one unrelated bipolar patients, 128 unrelated unipolar patients, and 262 controls were used in the study. There were no significant differences in DRD2 allele or genotype frequencies between the affective disorder and control groups. These results do not support a major role for the DRD2 gene in the etiology of either bipolar or unipolar affective disorders." [Abstract]

Ohara K, Nagai M, Tani K, Tsukamoto T, Suzuki Y, Ohara K.
Polymorphism in the promoter region of the alpha 2A adrenergic receptor gene and mood disorders.
Neuroreport 1998 May 11;9(7):1291-4
"Alpha 2 adrenergic receptors are thought to play a crucial role in the etiology or treatment of mood disorders. Polymorphism(s) in the promoter region of the alpha 2 receptor may affect the gene expression and be associated with mood disorders. We studied the previously reported polymorphisms of the alpha 2A receptor gene at position-1291 in 114 healthy controls and 103 mood disorder patients. There was statistically no difference between controls and patients in either the genotype or the allele frequency. There was statistically no difference between the genotype and the clinical characteristics. Our results suggest there is no association between this polymorphism in the promoter region of the alpha 2A receptor gene and mood disorders." [Abstract]

Takimoto T, Nakamura K, Ueno H, Matsuda M, Fukunishi I, Ameno K, Iwahashi K.
Major depression and heat shock protein 70-1 gene.
Clin Chim Acta 2003 Jun;332(1-2):133-7
"BACKGROUND: Heat shock protein (HSP) expression can be induced by any stress such as with adrenocorticotropic hormones and catecholamines. It has been reported that patients with major depression have a 162-base deletion in the 5'-flanking region of heat shock protein 70 (HSP70)-1 gene mRNA. METHODS: To detect the HSP70-1 gene mRNA, total RNA was isolated and amplified by RT-PCR, and the sequence was confirmed in all five patients by DNA direct sequencing analysis. RESULTS: RT-PCR produced was no deletions of 162 bp in the human heat shock protein 70-1 gene in any of the patients with major depression or the nine controls. CONCLUSION: This finding is inconsistent with previous reports. We suggest that the 162-base deletion in the 5'-flanking region of the HSP70-1 gene mRNA is not associated with major depression. Further studies are required to determine the amounts of HSP70 and its mRNA in stress disorders such as major depression." [Abstract]

Wesner RB, Tanna VL, Palmer PJ, Thompson RJ, Crowe RR, Winokur G.
Close linkage of esterase-D to unipolar depression and alcoholism is ruled out in eight pedigrees.
J Stud Alcohol 1991 Nov;52(6):609-12
"Unipolar depression and alcoholism were tested for genetic linkage to esterase-D at 13q14.1. Tight linkage to esterase-D was ruled out for three phenotypes using three models of penetrance: (1) unipolar depression and alcoholism taken together as affected, (2) unipolar depression alone as affected with alcoholism considered unaffected and (3) alcoholism alone as affected with unipolar depression considered unaffected. This study does not support an earlier finding of possible linkage between the esterase-D locus at 13q14.1 and alcoholism." [Abstract]

Wesner RB, Tanna VL, Palmer PJ, Goedken RJ, Crowe RR, Winokur G.
Linkage of c-Harvey-ras-1 and INS DNA markers to unipolar depression and alcoholism is ruled out in 18 families.
Eur Arch Psychiatry Neurol Sci 1990;239(6):356-60
"Eighteen families informative for c-Harvey-ras-1 and INS DNA markers were tested for linkage to unipolar depression and alcoholism. No evidence of linkage was found between these DNA markers and the disorders observed in the families. This study fails to replicate the Old Order Amish Study and suggests that a significant degree of genetic heterogeneity may be present among psychiatric disorders." [Abstract]

Hashimoto R, Suzuki T, Iwata N, Yamanouchi Y, Kitajima T, Kosuga A, Tatsumi M, Ozaki N, Kamijima K, Kunugi H
Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders.
J Neural Transm. 2005 Feb;112(2):303-7.
Two research groups have recently reported a significant association between schizophrenia and genetic variants of Frizzled-3 (FZD3) gene. We examined a possible association in a Japanese sample of schizophrenia, bipolar disorder, unipolar depression and controls with four single nucleotide polymorphisms (SNPs), tested in previous reports. We failed to find significant association in the four SNPs or haplotype analysis. The FZD3 gene might not play a role in conferring susceptibility to major psychosis in our sample. [Abstract]

->Back to Home<-

Recent Unipolar Depression Negative Association Research

1) Herbert J, Ban M, Brown GW, Harris TO, Ogilvie A, Uher R, Craig TK
Interaction between the BDNF gene Val/66/Met polymorphism and morning cortisol levels as a predictor of depression in adult women.
Br J Psychiatry. 2012 Jul 26;
BACKGROUND: Common genetic variants, such as the brain-derived neurotrophic factor (BDNF) Val/66/Met polymorphism (rs6265), are known to interact with environmental factors such as early adversity to increase the risk of subsequent major depression. Much less is known about how they interact with individual differences in cortisol, although these also represent a risk for major depression. AIMS: To determine whether this BDNF variant moderated the risk represented by higher levels of morning salivary cortisol in adult women. METHOD: We recruited 279 premenopausal women who were at high risk of major depressive disorder because of either negative self-evaluation, unsupportive core relationship or chronic subclinical symptoms of depression or anxiety. Morning salivary cortisol was measured daily for up to 10 days at entry. Participants were followed up for about 12 months by telephone calls at 3-4 monthly intervals. Major depression and severe life events were assessed through interviews at baseline and follow-up; DNA was obtained from the saliva. RESULTS: There were 53 onsets (19%) of depressive episodes during follow-up. There was a significant U-shaped relationship between adjusted morning cortisol levels at baseline and the probability of depression onset during follow-up. In total, 51% experienced at least one severe life event/difficulty, and this strongly predicted subsequent onsets of depressive episodes. The BDNF Val/66/Met genotype was not directly associated with onsets of depression or with cortisol levels, but there was significant interaction between Val/66/Met and cortisol: the association between baseline cortisol and depression was limited to those with the Val/66/Val variant. There was no interaction between life events and either this BDNF polymorphism or cortisol levels. CONCLUSIONS: Morning salivary cortisol interacts with the BDNF Val/66/Met polymorphism in predicting new depressive episodes. This paper adds to the evidence that single gene polymorphisms interact with endogenous factors to predict depression. [PubMed Citation] [Order full text from Infotrieve]

2) Bader V, Tomppo L, Trossbach SV, Bradshaw NJ, Prikulis I, Leliveld SR, Lin CY, Ishizuka K, Sawa A, Ramos A, Rosa I, García A, Requena JR, Hipolito M, Rai N, Nwulia E, Henning U, Ferrea S, Luckhaus C, Ekelund J, Veijola J, Järvelin MR, Hennah W, Korth C
Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.
Hum Mol Genet. 2012 Jul 13;
Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated association of physical and social anhedonia with the CRMP1 locus in a DISC1-dependent manner. Physical and social anhedonia are heritable traits, present as chronic negative symptoms of schizophrenia and severe major depression thus constituting a serious vulnerability factor for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role of a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of disease-associated epitope in post mortem brains, powered by a genetic association study is rapidly translated into a potential blood-based diagnostic marker. [PubMed Citation] [Order full text from Infotrieve]

3) Ota KT, Duman RS
Environmental and pharmacological modulations of cellular plasticity: Role in the pathophysiology and treatment of depression.
Neurobiol Dis. 2012 Jun 9;
Atrophy of neurons and gross structural alterations of limbic brain regions, including the prefrontal cortex (PFC) and hippocampus, have been reported in brain imaging and postmortem studies of depressed patients. Preclinical findings have suggested that prolonged negative stress can induce changes comparable to those seen in major depressive disorder (MDD), through dendritic retraction and decreased spine density in PFC and hippocampal CA3 pyramidal neurons. Interestingly, recent studies have suggested that environmental and pharmacological manipulations, including antidepressant medication, exercise, and diet, can block or even reverse many of the molecular changes induced by stress, providing a clear link between these factors and susceptibility to MDD. In this review, we will discuss the environmental and pharmacological factors, as well as the contribution of genetic polymorphisms, involved in the regulation of neuronal morphology and plasticity in MDD and preclinical stress models. In particular, we will highlight the pro-depressive changes incurred by stress and the reversal of these changes by antidepressants, exercise, and diet. [PubMed Citation] [Order full text from Infotrieve]

4) Ziv L, Muto A, Schoonheim PJ, Meijsing SH, Strasser D, Ingraham HA, Schaaf MJ, Yamamoto KR, Baier H
An affective disorder in zebrafish with mutation of the glucocorticoid receptor.
Mol Psychiatry. 2012 May 29;
Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how glucocorticoid signaling is linked to affective disorders. We identified an adult-viable zebrafish mutant in which the negative feedback on the stress response is disrupted, due to abolition of all transcriptional activity of GR. As a consequence, cortisol is elevated, but unable to signal through GR. When placed into an unfamiliar aquarium ('novel tank'), mutant fish become immobile ('freeze'), show reduced exploratory behavior and do not habituate to this stressor upon repeated exposure. Addition of the antidepressant fluoxetine to the holding water and social interactions restore normal behavior, followed by a delayed correction of cortisol levels. Fluoxetine does not affect the overall transcription of CRH, the mineralocorticoid receptor (MR), the serotonin transporter (Serta) or GR itself. Fluoxetine, however, suppresses the stress-induced upregulation of MR and Serta in both wild-type fish and mutants. Our studies show a conserved, protective function of glucocorticoid signaling in the regulation of emotional behavior and reveal novel molecular aspects of how chronic stress impacts vertebrate brain physiology and behavior. Importantly, the zebrafish model opens up the possibility of high-throughput drug screens in search of new classes of antidepressants.Molecular Psychiatry advance online publication, 29 May 2012; doi:10.1038/mp.2012.64. [PubMed Citation] [Order full text from Infotrieve]

5) Carballedo A, Amico F, Ugwu I, Fagan AJ, Fahey C, Morris D, Meaney JF, Leemans A, Frodl T
Reduced fractional anisotropy in the uncinate fasciculus in patients with major depression carrying the met-allele of the Val66Met brain-derived neurotrophic factor genotype.
Am J Med Genet B Neuropsychiatr Genet. 2012 Jul;159(5):537-48.
Experimental studies support a neurotrophic hypothesis of major depressive disorder (MDD). The aim of this study was to determine the effect of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism on the white matter fiber tracts connecting hippocampus and amygdala with the prefrontal lobe in a sample of patients with MDD and healthy controls. Thirty-seven patients with MDD and 42 healthy volunteers were recruited. Diffusion tensor imaging (DTI) data with 61 diffusion directions were obtained with MRI 3 Tesla scanner. Deterministic tractography was applied with ExploreDTI and Val66Met BDNF SNP (rs6265) was genotyped. Fiber tracts connecting the hippocampus and amygdala with the prefrontal lobe, namely uncinate fasciculus (UF), fornix, and cingulum were analyzed. A significant interaction was found in the UF between BDNF alleles and diagnosis. Patients carrying the BDNF met-allele had smaller fractional anisotropy (FA) in the UF compared to those patients homozygous for val-allele and compared to healthy subjects carrying the met-allele. A significant three-way interaction was detected between region of the cingulum (dorsal, rostral, and parahippocampal regions), brain hemisphere and BDNF genotype. Larger FA was detectable in the left rostral cingulum for met-allele carriers when compared to val/val alelle carriers. We provide evidence for the importance of the neurotrophic involvement in limbic and prefrontal connections. The met-allele of the BDNF polymorphism seems to render subjects more vulnerable for dysfunctions associated with the UF, a tract known to be related to negative emotional-cognitive processing bias, declarative memory problems, and autonoetic self awareness. © 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

6) Fanciulli M, Santulli L, Errichiello L, Barozzi C, Tomasi L, Rigon L, Cubeddu T, de Falco A, Rampazzo A, Michelucci R, Uzzau S, Striano S, de Falco FA, Striano P, Nobile C
LGI1 microdeletion in autosomal dominant lateral temporal epilepsy.
Neurology. 2012 Apr 24;78(17):1299-303.
[PubMed Citation] [Order full text from Infotrieve]

7) Hsu DT, Mickey BJ, Langenecker SA, Heitzeg MM, Love TM, Wang H, Kennedy SE, Pecińa M, Shafir T, Hodgkinson CA, Enoch MA, Goldman D, Zubieta JK
Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene influences fMRI signal responses during emotional stimulus processing.
J Neurosci. 2012 Feb 29;32(9):3253-60.
The corticotropin-releasing hormone (CRH) system coordinates neuroendocrine and behavioral responses to stress and has been implicated in the development of major depressive disorder (MDD). Recent reports suggest that GG-homozygous individuals of a single nucleotide polymorphism (rs110402) in the CRH receptor 1 (CRHR1) gene show behavioral and neuroendocrine evidence of stress vulnerability. The present study explores whether those observations extend to the neuronal processing of emotional stimuli in humans. CRHR1 was genotyped in 83 controls and a preliminary sample of 16 unmedicated patients with MDD who completed a functional magnetic resonance imaging scan while viewing blocks of positive, negative, and neutral words. In addition, potential mediating factors such as early life stress, sex, personality traits, and negative memory bias were examined. Robust differences in blood oxygenation level-dependent (BOLD) signal were found in healthy controls (A allele carriers > GG-homozygotes) in the right middle temporal/angular gyrus while subjects were viewing negative versus neutral words. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared with controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared with controls (n = 50) in the hypothalamus, bilateral amygdala, and left nucleus accumbens. Early life stress, personality traits, and levels of negative memory bias were associated with brain activity depending on genotype. Results from healthy controls and a preliminary sample of MDD participants show that CRHR1 single nucleotide polymorphism rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD. [PubMed Citation] [Order full text from Infotrieve]

8) Hing B, Davidson S, Lear M, Breen G, Quinn J, McGuffin P, MacKenzie A
A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.
Biol Psychiatry. 2012 Apr 1;71(7):618-26.
[PubMed Citation] [Order full text from Infotrieve]

9) Llorens-Martín M, Trejo JL
Mifepristone prevents stress-induced apoptosis in newborn neurons and increases AMPA receptor expression in the dentate gyrus of C57/BL6 mice.
PLoS One. 2011;6(11):e28376.
Chronic stress produces sustained elevation of corticosteroid levels, which is why it is considered one of the most potent negative regulators of adult hippocampal neurogenesis (AHN). Several mood disorders are accompanied by elevated glucocorticoid levels and have been linked to alterations in AHN, such as major depression (MD). Nevertheless, the mechanism by which acute stress affects the maturation of neural precursors in the dentate gyrus is poorly understood. We analyzed the survival and differentiation of 1 to 8 week-old cells in the dentate gyrus of female C57/BL6 mice following exposure to an acute stressor (the Porsolt or forced swimming test). Furthermore, we evaluated the effects of the glucocorticoid receptor (GR) antagonist mifepristone on the cell death induced by the Porsolt test. Forced swimming induced selective apoptotic cell death in 1 week-old cells, an effect that was abolished by pretreatment with mifepristone. Independent of its antagonism of GR, mifepristone also induced an increase in the percentage of 1 week-old cells that were AMPA(+). We propose that the induction of AMPA receptor expression in immature cells may mediate the neuroprotective effects of mifepristone, in line with the proposed antidepressant effects of AMPA receptor potentiators. [PubMed Citation] [Order full text from Infotrieve]

10) Shi C, Zhang K, Xu Q
Gender-specific role of the protein tyrosine phosphatase receptor type R gene in major depressive disorder.
J Affect Disord. 2012 Feb;136(3):591-8.
[PubMed Citation] [Order full text from Infotrieve]

11) Pae CU, Chiesa A, Porcelli S, Han C, Patkar AA, Lee SJ, Park MH, Serretti A, De Ronchi D
Influence of BDNF variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia.
Neuropsychobiology. 2012;65(1):1-11.
[PubMed Citation] [Order full text from Infotrieve]

12) Zannas AS, McQuoid DR, Steffens DC, Chrousos GP, Taylor WD
Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms.
Stress. 2012 Jul;15(4):425-34.
Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale?6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction. [PubMed Citation] [Order full text from Infotrieve]

13) Grabe HJ, Schwahn C, Mahler J, Appel K, Schulz A, Spitzer C, Fenske K, Barnow S, Freyberger HJ, Teumer A, Petersmann A, Biffar R, Rosskopf D, John U, Völzke H
Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Mar 30;36(2):264-70.
[PubMed Citation] [Order full text from Infotrieve]

14) Fujii T, Yamamoto N, Hori H, Hattori K, Sasayama D, Teraishi T, Hashikura M, Tatsumi M, Okamoto N, Higuchi T, Kunugi H
Support for association between the Ser205Leu polymorphism of p75(NTR) and major depressive disorder.
J Hum Genet. 2011 Nov;56(11):806-9.
Altered neurotrophin functions have been implicated in major depressive disorder (MDD). Previously, we reported an association between MDD and a missense polymorphism (Ser205Leu: rs2072446) of the gene encoding the p75 neurotrophin receptor (p75(NTR)). However, contradictive negative results have also been reported. This study tried to replicate the association in an independent sample. Subjects were 668 patients with MDD and 1130 healthy controls. The proportion of individuals carrying the Leu205 allele was significantly decreased in the patients than in the controls (?(2)=5.3, d.f.=1, P=0.021, odds ratio (OR) 0.74, 95% confidential interval (CI) 0.58-0.96). When allele frequencies were compared, the Leu205 allele was significantly reduced in the patients than in the controls (?(2)=4.4, d.f.=1, P=0.037, OR 0.78, 95% CI 0.61-0.99). When men and women were examined separately, there was a significant difference in genotype and allele distributions in women (genotype: ?(2)=8.3, d.f.=1, P=0.0039, OR 0.60, 95% CI 0.43-0.85; allele: ?(2)=7.3, d.f.=1, P=0.0069, OR 0.64, 95% CI 0.47-0.89), but not in men. The present study provided support for the previously reported association between the Ser205Leu polymorphism of the p75(NTR) gene and MDD, indicating that the Leu205 allele has a protective effect against the development of MDD, particularly in women. [PubMed Citation] [Order full text from Infotrieve]

15) Li W, Wang X, Zhao J, Lin J, Song XQ, Yang Y, Jiang C, Xiao B, Yang G, Zhang HX, Lv LX
Association study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population.
Genes Brain Behav. 2012 Feb;11(1):87-93.
Schizophrenia (SZ) is characterized by a variety of complex positive, negative and cognitive symptoms that are differentially expressed in individual patients. Variability in symptom presentation indicates that multiple genes, many involved in neurodevelopment, contribute to the etiology of SZ. The myelin transcription factor 1-like (MYT1L) gene encodes the MYT1L protein that participates in several neurodevelopment pathways. The copy number variant of MYT1L gene is associated with SZ, and single-nucleotide polymorphisms (SNPs) of MYT1L contribute to major depressive disorder. To explore the association of MYT1L polymorphisms with SZ, we examined six SNPs of MYT1L in a Han Chinese population consisting of 528 paranoid schizophrenic patients and 528 healthy subjects. Our results showed that rs17039584 was significantly associated with SZ (A>G), even after Bonferroni correction. When subjects were divided by gender, the rs10190125 allele and genotype remained significantly associated with SZ in female patients. Moreover, we found that rs6742365 was associated with a family history of SZ in females. Other SNPs did not achieve statistical significance for SZ but were associated with individual phenotypes, as measured by the Positive and Negative Syndrome Scale (PANSS) inventory. Our findings suggest that MYT1L may represent a susceptibility gene for SZ in the Han Chinese population and show that a specific SNP may increase susceptibility in females. [PubMed Citation] [Order full text from Infotrieve]

16) Fortier E, Noreau A, Lepore F, Boivin M, Pérusse D, Rouleau GA, Beauregard M
Early influence of the rs4675690 on the neural substrates of sadness.
J Affect Disord. 2011 Dec;135(1-3):336-40.
[PubMed Citation] [Order full text from Infotrieve]

17) Moon E, Rollins B, Mesén A, Sequeira A, Myers RM, Akil H, Watson SJ, Barchas J, Jones EG, Schatzberg A, Bunney WE, DeLisi LE, Byerley W, Vawter MP
Lack of association to a NRG1 missense polymorphism in schizophrenia or bipolar disorder in a Costa Rican population.
Schizophr Res. 2011 Sep;131(1-3):52-7.
A missense polymorphism in the NRG1 gene, Val>Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val>Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n=358), schizophrenia (SZ, n=273), or unrelated controls (CO, n=479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val>Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain-specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study. [PubMed Citation] [Order full text from Infotrieve]

18) Roussos P, Giakoumaki SG, Georgakopoulos A, Robakis NK, Bitsios P
The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males.
Bipolar Disord. 2011 May;13(3):250-9.
[PubMed Citation] [Order full text from Infotrieve]

19) Teyssier JR, Ragot S, Chauvet-Gélinier JC, Trojak B, Bonin B
Activation of a ΔFOSB dependent gene expression pattern in the dorsolateral prefrontal cortex of patients with major depressive disorder.
J Affect Disord. 2011 Sep;133(1-2):174-8.
[PubMed Citation] [Order full text from Infotrieve]

20) Kim HK, Kim SJ, Lee YJ, Lee HJ, Kang SG, Choi JE, Yun KW, Lim WJ
Influence of the interaction between the serotonin 1A receptor C-1019G polymorphism and negative life stressors on the development of depression.
Neuropsychobiology. 2011;64(1):1-8.
The current study aimed to investigate the interaction between the serotonin 1A receptor gene (HTR1A) C-1019G polymorphism and recent negative life stressors on depression in a Korean community sample. The HTR1A C-1019G polymorphism was genotyped in 416 community-dwelling Koreans (156 males, 260 females; 44.37 ± 14.67 years old). Lifetime and current major depressive episodes were diagnosed using the Structured Clinical Interview for DSM-IV. The Center for Epidemiological Studies for Depression Scale (CES-D) was self-applied and face-to-face interviews investigating negative life stressors within the last 6 months were also performed. The results indicated that there were significant interactions between the C-1019G polymorphism and negative life stressors on CES-D scores (p = 0.02) as well as on current major depressive episodes (p = 0.002), but not on past major depressive episodes. G carriers alone had higher CES-D scores and more frequently experienced major depressive episodes after stressors. The interaction between the C-1019G polymorphism in HTR1A and recent negative life stressors accounted for current major depressive episodes and depressive symptoms. Our findings suggest that people with this gene variant may be more susceptible to developing depression especially after negative life stressors. [PubMed Citation] [Order full text from Infotrieve]