Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ.
study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders,
age of onset and suicidal behavior.
"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."
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.
of unipolar major depressive disorder with genes of the serotonergic and dopaminergic
Mol Psychiatry 1999 Jul;4(4):389-92
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
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]
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.
Psychiatry 1997 Aug 15;42(4):282-5
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]
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.
"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]
K, Nagai M, Suzuki Y, Ohara K.
Low activity allele of catechol-o-methyltransferase
gene and Japanese unipolar depression.
"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,
Beta-1-adrenergic receptor gene in major depression: influence
on antidepressant treatment response.
Am J Med Genet. 2003
"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]
TY, Pae CU, Chae JH, Bahk WM, Kim KS, Pyo CW, Han H.
factor-beta gene polymorphism may not be associated with major depressive disorder
in the Korean population.
Psychiatry Clin Neurosci 2003
"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]
DG, Burchett BB, Fillenbaum GG.
APOE epsilon4 and low cholesterol
as risks for depression in a biracial elderly community sample.
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]
CJ, Wang YC, Tsai SJ.
Association study of angiotensin I-converting
enzyme polymorphism and symptomatology and antidepressant response in major depressive
J Neural Transm 2002 Sep;109(9):1209-14
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]
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.
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.
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]
TC, Schule C, Zwanzger P, Minov C, Zill P, Ella R, Eser D, Oezer S, Bondy B, Rupprecht
Hypothalamic-pituitary-adrenocortical axis dysregulation in patients
with major depression is influenced by the insertion/deletion polymorphism in
the angiotensin I-converting enzyme gene.
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]
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.
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."
E, Yamada K, Ebihara M, Toyota T, Nankai M, Shibuya H, Yoshikawa T.
study of the short tandem repeat in the 5' upstream region of the cholecystokinin
gene with mood disorders in the Japanese population.
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]
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
Am J Med Genet 2002 Jul 8;114(5):519-22
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]
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.
study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders.
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]
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
Psychiatry Clin Neurosci 2002 Apr;56(2):177-80
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."
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.
of a naturally occurring polymorphism in the promoter region of the norepinephrine
transporter and analysis in major depression.
"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]
D, Du L, Bakish D, Lapierre YD, Hrdina PD.
gene polymorphism is not associated with susceptibility to major depression.
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]
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
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]
YW, Chen TJ, Wang YC, Liou YJ, Hong CJ, Tsai SJ.
for neuronal nitric oxide synthase gene polymorphism with major depression and
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.
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
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
Rujescu D, Giegling I, Sato T, Moeller HJ.
polymorphism in the promoter of the serotonin transporter gene is not associated
with suicidal behavior.
Psychiatr Genet 2001 Sep;11(3):169-72
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
TY, Pae CU, Chae JH, Bahk WM, Kim KS.
Polymorphism of CTLA-4 gene
for major depression in the Korean population.
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
"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.
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.
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]
J, Bandelow B, Ruther E, Kornhuber J.
Polymorphism of the gene of
angiotensin converting enzyme: lack of association with mood disorder.
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."
RA, Keramatipour M, Ho LW, Rubinsztein JS, Michael A, Walsh C, Paykel ES, Rubinsztein
No association of an insertion/deletion polymorphism in the angiotensin
I converting enzyme gene with bipolar or unipolar affective disorders.
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]
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.
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]
PH, Oren DA, Malison R, Price LH, Rosenbaum J, Smoller J, Charney DS, Gelernter
Genetic polymorphism at the CLOCK gene locus and major depression.
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>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]
CJ, Tsai SJ, Cheng CY, Liao WY, Song HL, Lai HC.
of the 5-HT(6) receptor polymorphism (C267T) in mood disorders.
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."
YY, Grailhe R, Arango V, Hen R, Mann JJ.
Relationship of psychopathology
to the human serotonin1B genotype and receptor binding kinetics in postmortem
Neuropsychopharmacology 1999 Aug;21(2):238-46
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]
A, Macciardi F, Cusin C, Lattuada E, Lilli R, Di Bella D, Catalano M, Smeraldi
GABAA alpha-1 subunit gene not associated with depressive symptomatology
in mood disorders.
Psychiatr Genet 1998 Winter;8(4):251-4
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]
J, Sanacora G, Kranzler HR, Malison R, Hibbard ES, Price LH, Krystal J, Gelernter
Mutation screen of the glutamate decarboxylase-67 gene and haplotype
association to unipolar depression.
Am J Med Genet. 2004
"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
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.
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]
H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T, Hirose T, Nanko S.
polymorphism in methylenetetrahydrofolate reductase gene and psychoses.
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
RA, Coleman TA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC.
association of a functional polymorphism in the dopamine D2 receptor promoter
region with bipolar or unipolar affective disorders.
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]
K, Nagai M, Tani K, Tsukamoto T, Suzuki Y, Ohara K.
in the promoter region of the alpha 2A adrenergic receptor gene and mood disorders.
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]
T, Nakamura K, Ueno H, Matsuda M, Fukunishi I, Ameno K, Iwahashi K.
depression and heat shock protein 70-1 gene.
Clin Chim Acta
"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]
RB, Tanna VL, Palmer PJ, Thompson RJ, Crowe RR, Winokur G.
linkage of esterase-D to unipolar depression and alcoholism is ruled out in eight
J Stud Alcohol 1991 Nov;52(6):609-12
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]
RB, Tanna VL, Palmer PJ, Goedken RJ, Crowe RR, Winokur G.
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
"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
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]