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Zill P, Baghai TC, Zwanzger P, Schule C, Minov C, Riedel M,
Neumeier K, Rupprecht R, Bondy B.
Evidence for an association between
a G-protein beta3-gene variant with depression and response to antidepressant
treatment.
Neuroreport 2000 Jun 26;11(9):1893-7
"Abnormal
signal transduction pathways have been implicated in the pathogenesis of bipolar
disorder and major depression. G-proteins are key elements of these pathways in
the regulation of cellular responses by transmission of signals from receptors
to effector proteins. In recent years several studies have reported altered levels
and activities of G-protein alpha subunits in depressive patients. A recently
identified polymorphism of a G-protein beta3 subunit (C825T) has been shown to
be associated with increased signal transduction and ion transport activity. Therefore,
we investigated whether this Gbeta3 polymorphism is associated with affective
disorders or with the response to antidepressant treatment in 88 depressive patients
(10 bipolar disorder, 78 major depression) compared with 68 schizophrenic patients
and 111 healthy controls. We found a significantly higher frequency of the T allele
in depressive patients than in healthy controls (genotype: chi2 = 9.571, df =
2, p = 0.008; alleles: p = 0.004, OR = 1.87, 95% CI 1.23-2.84; Fisher's exact
test, two sided) and schizophrenic patients (genotype: chi2 = 8.037, df = 2, p
= 0.018; alleles: p = 0.009, OR = 1.94, 95% CI 1.99-3.14; Fisher's exact test,
two sided). We also found a statistical significant association between TT homozygosity
and response to antidepressant treatment after four weeks (p = 0.01). The results
of this study suggest that the investigated G-protein beta3 subunit seems to be
a susceptibility factor for major depression and maybe even for bipolar disorder,
but not for schizophrenia. Further, the presence of the T allele could be an indicator
for treatment response." [Abstract] Lee
HJ, Cha JH, Ham BJ, Han CS, Kim YK, Lee SH, Ryu SH, Kang RH, Choi MJ, Lee MS.
Association
between a G-protein beta3 subunit gene polymorphism and the symptomatology and
treatment responses of major depressive disorders.
Pharmacogenomics
J. 2004;4(1):29-33.
"The genes involved in signal transduction are major
candidates in association studies on affective disorders and responses to antidepressants.
We investigated whether the C825T polymorphism of the beta3 subunit of G protein
(GNB3) gene is associated with the symptom severity or treatment response of major
depressive disorders (MDDs) in a Korean sample of 106 MDD patients; our study
also included 133 healthy controls. Hypertensive subjects were excluded from the
study because association between GNB3 variants and hypertension has been reported
in previous studies. We found significantly more carriers of the 825T allele in
MDD patients than in normal controls (chi(2)=6.37, P=0.012; OR=2.19, 95% CI 1.18-4.05).
The T-allele carriers showed higher scores than those with the CC genotype in
the baseline total and in some subcategories of the Hamilton Depression Rating
Scale (P<0.05). We also found a statistically significant association between
T-allele carriers and antidepressant treatment response (P<0.05). These results
suggest that the T allele of the C825T polymorphism in the GNB3 gene is associated
with MDD. It was also demonstrated that MDD patients bearing the T allele had
a severe symptomatology and a better response to antidepressant treatment than
patients without the T allele." [Abstract]
Serretti A, Lorenzi C, Cusin C, Zanardi R, Lattuada
E, Rossini D, Lilli R, Pirovano A, Catalano M, Smeraldi E.
SSRIs
antidepressant activity is influenced by G beta 3 variants.
Eur
Neuropsychopharmacol 2003 Mar;13(2):117-22
"The aim of the present study
was to test a possible effect of the G-protein beta3-subunit (Gbeta3) C825T gene
variant on the antidepressant activity of selective serotonin reuptake inhibitors
(SSRIs) in a sample of major and bipolar depressives, with or without psychotic
features. Four hundred and ninety inpatients were treated with fluvoxamine 300
mg/day (n=362) or paroxetine 40 mg/day (n=128) and either placebo or pindolol
in a double-blind design for 6 weeks. The severity of depressive symptoms was
weekly assessed with the Hamilton Rating Scale for Depression. Gbeta3 allelic
variants were determined in each subject using a PCR-based technique. Subjects
with Gbeta3 T/T variants showed better response to treatment (P=0.009) and this
effect was independent from analyzed demographic and clinical variables. These
results confirm preliminary reports and shed further light on the genetics of
the response to antidepressant treatments." [Abstract] Exton
MS, Artz M, Siffert W, Schedlowski M.
G protein beta3 subunit 825T
allele is associated with depression in young, healthy subjects.
Neuroreport
2003 Mar 3;14(3):531-3
"This study investigated the relationship between
the G protein beta3 subunit 825T allele and depression in young, healthy subjects.
825T and 825C allele carriers were characterized among 190 healthy medical students.
State depression was assessed by the Becks Depression Inventory, supplemented
by subscales of the Freiburg Personality Inventory, and Questionnaire for Measuring
Factors of Aggression which assess trait depression. Depression of homo- and heterozygous
825T allele carriers was compared to 825C allele carriers via multi-level statistical
analysis. 825T allele carriers displayed higher levels of depression, as measured
by each questionnaire. Regression analysis demonstrated that allele type was the
single predictor of depression. The predictive capacity of the 825T allele in
depression was further supported by odds-ratio analysis. We conclude that the
G protein beta3 subunit 825T allele is predictive of depressive mood in a young,
healthy population." [Abstract] Joyce
PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, Kennedy MA.
Age-dependent
antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and
G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline.
Int
J Neuropsychopharmacol. 2003 Dec;6(4):339-46.
"In 169 depressed patients
randomized to treatment with either fluoxetine or nortriptyline, we examined whether
polymorphisms of the serotonin transporter and the G protein beta3 subunit influenced
response to these antidepressants. For depressed patients under the age of 25
yr the T allele of the G protein beta3 subunit was associated with a markedly
poorer response to nortriptyline, while serotonin transporter polymorphisms did
not predict antidepressant response. However, in patients 25 yr or older, the
G protein beta3 polymorphisms did not predict antidepressant response, while the
s,s genotype of the serotonin transporter was associated with a poorer response
to both fluoxetine and nortriptyline. These differential pharmacogenetic predictors
of antidepressant response by age, may provide clues to understanding the discontinuities
in pharmacological responsiveness of child/adolescent and adult depressive disorders."
[Abstract]
Bondy
B, Baghai TC, Zill P, Bottlender R, Jaeger M, Minov C, Schule C, Zwanzger P, Rupprecht
R, Engel RR.
Combined action of the ACE D- and the G-protein beta3
T-allele in major depression: a possible link to cardiovascular disease?
Mol
Psychiatry 2002;7(10):1120-6
"Although it is well established that depression
is a major risk factor for the development of coronary artery disease and that
cerebrovascular disease can be a major contributing factor for the development
of depression, the information about the interplay between the central nervous
system and cardiovascular disease is still limited. We investigated the angiotensin
I converting enzyme (ACE) ID and the G-protein beta3-subunit (Gbeta3) C825T polymorphism
in 201 patients with unipolar major depression and 161 ethnically and age-matched
controls. Both gene variants have earlier been associated with either cardiovascular
disease or affective disorders, making them good candidates for a combined analysis.
We found a significant increase in the Gbeta3 T allele (OR = 1.61, 95% CI 1.17-2.2,
P = 0.0035) and a marginal altered genotype distribution of the ACE ID polymorphism
with decrease in the II genotypes (chi(2) = 6.43, df=3, P = 0.04) in the patients'
group. Analysing the data for both genes we found that the combined actions of
ACE and Gbeta3 genotypes accumulate in carriers of the ACE D allele (ID and DD)
and Gbeta3 TT homozygotes with ID/DD-TT carriers showing a more than five-fold
increase in risk for major depression (crude OR = 5.83, 95% CI 1.99-17.08, P =
0.0002). As our study was carried out with depressive patients without serious
cardiac impairment at the time of the investigation, we are presently unable to
predict whether this combined action of the ACE ID/DD-Gbeta3 TT genotype is increasing
the risk for both disorders. Nevertheless our study reports for the first time
that the same allelic combination of two genes that have been shown to increase
the risk for myocardial infarction (Naber et al, 2000) increase the vulnerability
for depressive disorder." [Abstract]
Baghai TC, Schule C, Zill P, Deiml T, Eser D, Zwanzger P, Ella R, Rupprecht R, Bondy B
The angiotensin I converting enzyme insertion/deletion polymorphism influences therapeutic outcome in major depressed women, but not in men.
Neurosci Lett. 2004 Jun 3;363(1):38-42.
Angiotensin converting enzyme (ACE) is expressed in the central nervous system (CNS), where its primary function comprises degradation of neuropeptides including substance P (SP). Because of the possible antidepressant effects of SP antagonists, the influence of SP on both pathophysiology and mitigation of depression has been hypothesized. It was shown that ACE plasma concentration is determined by an insertion/deletion (I/D) polymorphism represented by the presence or absence of a 287 bp DNA fragment within the ACE gene. Because the D allele was associated with higher ACE levels this may have a positive impact on the therapeutic efficacy of antidepressant treatment. Thus, variations in CNS expression of ACE might influence the response to various antidepressant therapies. We could show a divergent clinical outcome in relation to different genotypes in 313 depressed patients who were treated with various antidepressants. A lower HAM-D17 score after 4 weeks of treatment in D/D and I/D in comparison to I/I genotypes was detected; the duration of hospitalization was shorter in D allele carriers. The D allele seems to be a predictor for a faster onset of different antidepressant therapies. The patients' gender influences these outcome effects significantly. After subdivision of the patients according to their gender only female patients contributed significantly to the genotype dependent therapeutic outcome. Our investigation gives the first hint that the speed of onset of antidepressant therapies may be dependent on both variants of the ACE genes and the gender of the patients. [Abstract]
Kunugi H, Kato T, Fukuda R, Tatsumi M, Sakai T, Nanko
S.
Association study of C825T polymorphism of the G-protein b3 subunit
gene with schizophrenia and mood disorders.
J Neural Transm
2002 Feb;109(2):213-8
"Alterations of G proteins have been implicated
in major psychiatric illnesses. A C825T polymorphism of a gene encoding the beta3
subunit of heterotrimeric G proteins (GNB3) was reported to be associated with
several pathological conditions, such as hypertension and depressive disorder.
We examined whether this polymorphism is associated with functional psychoses
in a Japanese sample of 370 schizophrenics, 164 bipolars, 68 depressive patients,
and 198 controls. We obtained no evidence for an association of the polymorphism
with any diagnostic group." [Abstract]
Lin
CN, Tsai SJ, Hong CJ.
Association analysis of a functional G protein
beta3 subunit gene polymorphism (C825T) in mood disorders.
Neuropsychobiology
2001;44(3):118-21
"The guanine nucleotide-binding proteins (G proteins),
heterotrimers consisting of alpha, beta and gamma subunits, convey signals initiated
by the activation of many neurotransmitter receptors. Evidence for involvement
of the G proteins in mood disorders relies on the effects of mood stabilizers
and antidepressants on G protein function. In addition, abnormalities in the expression
of G proteins have been demonstrated in mood disorder patients. Therefore, we
tested the hypothesis that a functional polymorphism (C825T) in the G protein
beta3 gene subunit (GNB3) confers susceptibility to mood disorders. A population-based
association study was utilized, and GNB3 was genotyped for 144 mood disorder patients
and 153 normal controls. The results reveal that it is not likely that the C825T
polymorphism in the GNB3 gene subunit is involved in mood disorder pathogenesis.
Further studies of the associations between other G protein subunits and mood
disorder are needed to fully elaborate the involvement of this protein in mood
disorders." [Abstract]
Willeit M, Praschak-Rieder N, Zill P, Neumeister
A, Ackenheil M, Kasper S, Bondy B.
C825T polymorphism in the G protein
beta3-subunit gene is associated with seasonal affective disorder.
Biol
Psychiatry. 2003 Oct 1;54(7):682-6.
"BACKGROUND: Heterotrimeric G proteins
play a pivotal role in the intracellular transduction of many transmitter-receptor
interactions. Alterations in signal transduction and in G protein concentrations
have been reported in seasonal and nonseasonal affective disorder. A single-nucleotide
polymorphism (C825T) in the G protein beta3-subunit gene has been shown to influence
intracellular response to G protein-coupled stimuli, and the T-allele of this
polymorphism has been associated with hypertension and major depression. METHODS:
We genotyped deoxyribonucleic acid from peripheral mononuclear cells of 172 patients
with seasonal affective disorder, winter type (SAD), and 143 healthy control subjects.
RESULTS: Patients with SAD were significantly more likely to be either homo- or
heterozygous for the G(beta)3 T-allele when compared with healthy control subjects
(p =.001), and they displayed a higher frequency of the G(beta)3 C825T T-allele
(p =.021). The polymorphism was not associated with seasonality, which is the
tendency to experience variations in mood and behavior with changing of the seasons.
CONCLUSIONS: The G(beta)3 C825T polymorphism was associated with SAD in our study
sample. This finding strengthens the evidence for the involvement of G protein-coupled
signal transduction in the pathogenesis of affective disorder." [Abstract]
Zubenko GS, Hughes HB 3rd, Maher BS, Stiffler JS,
Zubenko WN, Marazita ML.
Genetic linkage of region containing the
CREB1 gene to depressive disorders in women from families with recurrent, early-onset,
major depression.
Am J Med Genet 2002 Dec 8;114(8):980-7
"This
report describes the results of a model-free linkage analysis of six polymorphic
markers, located in a 15 cM region of chromosome 2q33-35, and unipolar Mood Disorders
in 81 families identified by probands with Recurrent, Early-Onset Major Depressive
Disorder (RE-MDD), a severe and familial form of clinical depression. Our findings
reveal significant evidence of linkage of unipolar Mood Disorders to a 451 Kb
region of 2q33-34 flanked by D2S2321 and D2S2208 in these families. Increasing
peak LOD scores were observed in both the single point and multipoint analyses
for Mood Disorder phenotypes whose definitions embodied progressively less stringent
severity criteria for inclusion in the affected group. The sex-dependent multipoint
linkage analysis of any Major or Minor Mood Disorders produced LOD scores that
reached 6.331 and 6.866 at D2S2321 and D2S2208, respectively. Linkage of Mood
Disorders to this region was observed exclusively among female affected relative
pairs; no suggestion of linkage was observed when male affected relative pairs
were analyzed. These observations imply that a sex-specific susceptibility gene
in this region contributes to the vulnerability of women in these families to
the development of unipolar Mood Disorders that ranged in severity from minor
to severe at the time of clinical assessment. The region between the markers that
yielded the peak LOD score includes the CREB1 gene, which encodes a cAMP-responsive
element-binding protein (CREB) that is a member of the bZIP family of transcription
factors. Based on considerable clinical and preclinical evidence, CREB1 is an
attractive candidate for a susceptibility gene for unipolar Mood Disorders. The
sex-specificity of the susceptibility locus identified by our study may result
from reported synergistic interactions of CREB with nuclear estrogen receptors."
[Abstract] Zubenko
GS, Maher B, Hughes HB 3rd, Zubenko WN, Stiffler JS, Kaplan BB, Marazita ML.
Genome-wide
linkage survey for genetic loci that influence the development of depressive disorders
in families with recurrent, early-onset, major depression.
Am
J Med Genet. 2003 Nov 15;123B(1):1-18.
"In this report, we describe the
results of the first genome-wide linkage survey for genetic loci that influence
the development of unipolar Mood Disorders in 81 families identified by individuals
with Recurrent, Early-Onset, Major Depressive Disorder (RE-MDD). Model-free linkage
analysis was performed using genotypes for 392 highly informative polymorphisms
with an average spacing of 9 cM. The highest maximum LOD score observed, 8.19
(genome-wide adjusted P << 0.0001), occurred for Recurrent Major Depressive
Disorder (R-MDD) at D2S2321 (205 cM), located 121 kb proximal to CREB1. Nineteen
chromosomal regions contained linkage peaks that reached genome-wide statistical
significance (genome-wide adjusted P < 0.05) and ten of these were "highly
significant" (adjusted P < 0.001). Six of the 19 linkage peaks were revealed
only when the analysis included covariates to control for the effects of sex and
linkage to CREB1. Sex-specific susceptibility loci were common and preferentially
affected the vulnerability of women to developing unipolar Mood Disorders. Five
loci revealed evidence of interaction with the CREB1 locus in determining susceptibility
(epistasis). A systematic candidate gene analysis is presented and potential overlaps
of the linkage regions for unipolar Mood Disorders with those reported for other
psychiatric disorders are discussed. The findings suggest that genes whose products
participate in cellular signaling pathways that converge on CREB, as well as the
target genes whose expression they regulate, may also harbor alleles that affect
the development of Mood Disorders and related conditions." [Abstract]
Kunugi H, Hashimoto R, Yoshida M, Tatsumi M, Kamijima K
A missense polymorphism (S205L) of the low-affinity neurotrophin receptor p75NTR gene is associated with depressive disorder and attempted suicide.
Am J Med Genet. 2004 Aug 15;129B(1):44-6.
Several lines of evidence have implicated that neurotrophins play an important role in the pathophysiology of mood disorders. This study examined whether a common missense polymorphism (S205L) of a gene encoding the p75NTR, the low-affinity receptor for neurotrophins, is associated with depressive disorder in a Japanese sample of 164 patients and the same number of controls matched for age and sex. There were significant differences in the genotype distribution and allele frequency between the cases and controls. The minor allele (L205) was significantly decreased in the patients than in the controls (P < 0.05, odds ratio 0.54, 95% CI 0.31-0.94), suggesting that this allele may have a protective effect against the development of major depression. Furthermore, this association was more strongly observed in the patients with a history of attempted suicide than those without such a history. Our results suggest that the S205L polymorphism of the p75NTR gene is involved in the pathogenesis of depressive disorder and suicidal behavior. [Abstract]
Tsai
SJ, Wang YC, Hong CJ, Chiu HJ.
Association study of oestrogen receptor
alpha gene polymorphism and suicidal behaviours in major depressive disorder.
Psychiatr Genet 2003 Mar;13(1):19-22
"OBJECTIVE Gender comparison in epidemiological
studies has consistently demonstrated a greater prevalence for major depressive
disorders (MDD) in females. Several lines of evidence have implicated oestrogen
pathways in this gender difference. Furthermore, there is evidence that attempted
suicides are more frequent in women. A population-based association study was
used to test the hypothesis that the genetic variants ( II and I polymorphisms)
of the oestrogen receptor alpha gene (ER-alpha) confer susceptibility to MDD.METHODS
The ER-alpha was genotyped for 154 patients with MDD and 226 controls in a Chinese
population.RESULTS Statistical analysis showed a significant difference in the
II genotype and allele frequencies between the female MDD patients and the female
controls ( =0.010 and =0.004, respectively). However, no significant differences
in ER-alpha genotype or allele frequencies were found between male MDD patients
and male controls. Furthermore, the ER-alpha genotypes were not associated with
suicide-attempt history for MDD cases.CONCLUSIONS Our results suggest that the
ER-alpha may play a role in the susceptibility of MDD in females." [Abstract]
Kelly CB, McDonnell AP, Johnston TG, Mulholland C, Cooper SJ, McMaster D, Evans A, Whitehead AS
The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland.
J Psychopharmacol. 2004 Dec;18(4):567-71.
Low plasma folate and its derivatives have been linked with depressive disorders in studies dating back over 30 years. A thermolabile variant (677C->T) of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in a cohort of patients (mean age 48 years) with depressive disorder (n = 100) were compared with those in age- and sex-matched controls. Serum levels of folate, homocysteine and vitamin B(12) were also compared between groups. The thermolabile variant of MTHFR was significantly more common in the group with a history of depressive disorder (P= 0.03). Serum levels of folate, homocysteine and vitamin B(12) did not differ significantly between groups. A MTHFR C677T genotype is associated with increased risk of depressive episodes in this homogenous patient population. [Abstract]
Bjelland
I, Tell GS, Vollset SE, Refsum H, Ueland PM.
Folate, Vitamin B12,
Homocysteine, and the MTHFR 677C->T Polymorphism in Anxiety and Depression:
The Hordaland Homocysteine Study.
Arch Gen Psychiatry. 2003
Jun;60(6):618-26.
"BACKGROUND: An association between depression and folate
status has been demonstrated in clinical studies, whereas data are sparse on the
relationship between depression and other components of 1-carbon metabolism such
as vitamin B12, homocysteine, and the methylenetetrahydrofolate reductase 677C-->T
polymorphism. The relationship between anxiety and these components is less well
known. This study examined the associations between folate, total homocysteine,
vitamin B12, and the methylenetetrahydrofolate reductase 677C-->T polymorphism,
and anxiety and depression in a large population-based study. METHODS: Anxiety
and depression, measured by the Hospital Anxiety and Depression Scale, were assessed
in 5948 subjects aged 46 to 49 years (mean, 47.4 years) and 70 to 74 years (mean,
71.9 years) from the Hordaland Homocysteine Study cohort. By means of logistic
regression models, anxiety and depression scores were examined in relation to
the factors listed above. RESULTS: Overall, hyperhomocysteinemia (plasma total
homocysteine level >/=15.0 micro mol/L [>/=2.02 mg/dL]) (odds ratio, 1.90;
95% confidence interval, 1.11-3.25) and T/T methylenetetrahydrofolate reductase
genotype (odds ratio, 1.69; 95% confidence interval, 1.09-2.62), but not low plasma
folate or vitamin B12 levels, were significantly related to depression without
comorbid anxiety disorder. Plasma folate level was inversely associated with depression
only in the subgroup of middle-aged women. None of the investigated parameters
showed a significant relationship to anxiety. CONCLUSION: Our results provide
further evidence of a role of impaired 1-carbon metabolism in depression."
[Abstract]
Tan EC, Chong SA, Lim LC, Chan AO, Teo YY, Tan CH, Mahendran R
Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders.
Psychiatr Genet. 2004 Dec;14(4):227-31.
OBJECTIVE: An elevated homocysteine level has been reported for patients with schizophrenia and depression. We investigated the frequency of the common C667 T variant of the enzyme methylenetetrahydrofolate reductase in controls and patients of Chinese descent. METHODS: Controls with no history of mental disorder and patients diagnosed with schizophrenia, bipolar and unipolar disorders were recruited. Genomic DNA from all were genotyped for the C667 T polymorphism by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There was no significant difference in genotype distributions or allele frequencies between controls and any of the diagnostic groups, although the frequency of the T allele was higher for all diagnostic groups and for both the male and female genders. When data was analyzed with the minor T allele as dominant, there was an excess of the T-containing genotypes in each of the patient groups compared with controls. For the difference between controls and all cases combined it almost reached statistical significance (P=0.077), with an odds ratio of 1.46 (95% confidence interval, 0.96-2.22). CONCLUSIONS: Although there was no significant association as measured by the P value, the odds ratio and confidence interval provided some evidence of increased risk for individuals with the T-containing genotypes. A minor role for this polymorphism in the pathogenesis of schizophrenia and depression could not be ruled out and would warrant further investigation. [Abstract]
Wang JC, Hinrichs AL, Stock H, Budde J, Allen R, Bertelsen S, Kwon JM, Wu W, Dick DM, Rice J, Jones K, Nurnberger JI, Tischfield J, Porjesz B, Edenberg HJ, Hesselbrock V, Crowe R, Schuckit M, Begleiter H, Reich T, Goate AM, Bierut LJ
Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome.
Hum Mol Genet. 2004 Sep 1;13(17):1903-11.
Several correlated phenotypes, alcohol dependence, major depressive syndrome,
and an endophenotype of electrophysiological measurements, event-related
oscillations (EROs), have demonstrated linkage on the long arm of chromosome 7.
Recently, we reported both linkage and association between polymorphisms in the
gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) and EROs. In this
study, we evaluated whether genetic variation in the CHRM2 gene is also a risk
factor for the correlated clinical characteristics of alcoholism and depression.
The CHRM2 gene contains a single coding exon and a large 5' untranslated region
encoded by multiple exons that can be alternatively spliced. Families were
recruited through an alcohol dependent proband, and multiplex pedigrees were
selected for genetic analyses. We examined 11 single nucleotide polymorphisms
(SNPs) spanning the CHRM2 gene in these families. Using the UNPHASED pedigree
disequilibrium test (PDTPHASE), three SNPs (one in intron 4 and two in intron 5)
showed highly significant association with alcoholism (P=0.004-0.007). Two SNPs
(both in intron 4) were significantly associated with major depressive syndrome
(P=0.004 and 0.017). Haplotype analyses revealed that the most common haplotype
(>40% frequency), T-T-T (rs1824024-rs2061174-rs324650), was under-transmitted to affected individuals with alcohol dependence and major depressive syndrome. Different complementary haplotypes were over-transmitted in alcohol dependent and depressed individuals. These findings provide strong evidence that variants within or close to the CHRM2 locus influence risk for two common psychiatric disorders. [Abstract]
Comings
DE, Wu S, Rostamkhani M, McGue M, Iacono WG, MacMurray JP.
Association
of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in
women.
Am J Med Genet 2002 Jul 8;114(5):527-9
"Cholinergic
neurons have been implicated in depression and in the disorders of REM sleep in
depression. We examined a common A-> T 1890 polymorphism in the 3' UTR of the
cholinergic muscarinic receptor 2 (CHRM2) gene. There was a significant increase
in the frequency of 11 homozygotes in 126 women with major depression (43.7%)
compared to 304 women without major depression (25.7%), P =.001. There was no
increase in the frequency of 11 homozygotes in 52 men with depression (26.9%)
compared to 278 men without depression (27.7%). Regression analysis, scoring subjects
with the 11 genotype as 1, and those with other genotypes as 0, showed that in
women r(2) =.030, F = 13.37, P =.0003. By contrast, in men r(2) =.00001, F = 0.002,
P =.96. These results are consistent with a gender-specific role of the CHRM2
gene in depression in women." [Abstract]
Massat I, Souery D, Del-Favero J, Nothen M, Blackwood D, Muir W, Kaneva R, Serretti A, Lorenzi C, Rietschel M, Milanova V, Papadimitriou GN, Dikeos D, Van Broekhoven C, Mendlewicz J
Association between COMT (Val(158)Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study.
Mol Psychiatry. 2004 12 7;
The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders. [Abstract]
Zubenko
GS, Hughes III HB, Stiffler JS, Zubenko WN, Kaplan BB.
D2S2944 identifies
a likely susceptibility locus for recurrent, early-onset, major depression in
women.
Mol Psychiatry 2002;7(5):460-7
"Recurrent,
early-onset, major depressive disorder (RE-MDD) is a strongly familial condition
whose malignant effects have a significant negative impact on the health and longevity
of patients and their family members. Sixteen of the 19 candidate susceptibility
loci identified by a recent genome survey revealed allelic associations with RE-MDD
in men or women, but not in both sexes. The association of D2S2944 alleles and
genotypes with RE-MDD and related disorders was evaluated using a case-control
study design employing 100 adults with RE-MDD and 100 adult controls who had no
personal or family history of mental disorders. The results of the case-control
study were subsequently evaluated in a sample of 81 families ascertained through
probands with RE-MDD using the transmission/disequilibrium test. The frequency
of the D2S2944 124-bp allele among women with RE-MDD was approximately three times
that for female controls (P = 0.0003). Women who carried the D2S2944 124-bp allele
revealed a significantly elevated risk of developing RE-MDD, as indicated by an
odds ratio of 4.5 compared to female controls (P<0.001). In contrast, men with
RE-MDD did not have an increased frequency of this allele compared to male controls,
and men who were carriers did not exhibit an increased risk of developing RE-MDD
or related disorders. Our findings also suggest that the D2S2944 124-bp allele
increases the risk of alcohol and other substance use disorders among women with
RE-MDD. The transmission/disequilibrium test provided confirmatory evidence of
these sex-specific findings within families. The results of this study confirm
the existence of sex-specific susceptibility loci for RE-MDD, and suggest that
there may be important differences in the molecular pathophysiology of RE-MDD
in men and women. Alternatively, our findings may reflect the existence of sex-specific
differences in the molecular mechanisms that determine resilience to endogenous
or environmental depressogenic stimuli. The identification and characterization
of the D2S2944 susceptibility locus for RE-MDD and related substance use disorders
is likely to provide important new insights into the clinical biology, treatment,
and prevention of these disorders." [Abstract] Philibert
R, Caspers K, Langbehn D, Troughton EP, Yucuis R, Sandhu HK, Cadoret RJ.
The
association of the D2S2944 124 bp allele with recurrent early onset major depressive
disorder in women.
Am J Med Genet. 2003 Aug 15;121B(1):39-43.
"Major
depressive disorder (MDD) and substance use disorders (SUD) are complex behavioral
disorders with 40-50% heritability. Recently, Zubenko and colleagues reported
that the 124 bp allele of D2S2944, a tetranucleotide repeat marker on 2q35, is
strongly associated with recurrent, early onset MDD (RE-MDD) and alcohol use disorders
in women. To test this hypothesis, we examined the association of the 124 bp allele
in a subset of 171 adoptees from the Iowa Adoption Studies, a population with
high rates of MDD and SUD. We report that in our population, the 124 bp allele
significantly associated with RE-MDD in women. There was slight evidence of an
increased of SUD in women with the 124 bp allele with the rate of cannabis use
disorders reaching statistical significance (P < 0.04) before correction for
multiple comparisons. Given the history of prior studies implicating 2q35 as a
locus encoding vulnerability to co-morbid alcoholism and depression, these findings
strongly suggest that sequence variation conveying increased susceptibility to
MDD and possibly SUD is in close proximity to D2S2944." [Abstract] Zubenko
GS, Hughes HB, Stiffler JS, Zubenko WN, Kaplan BB.
Genome survey
for susceptibility loci for recurrent, early-onset major depression: results at
10cM resolution.
Am J Med Genet 2002 May 8;114(4):413-22
"Recurrent
(two or more episodes), early-onset (first episode at < or = 25 years) major
depressive disorder (RE-MDD) is a strongly familial condition (lambda(first-degree
relatives) = 8) whose malignant effects have a significant negative impact on
the health and longevity of patients and their family members. The goal of this
study was to identify candidate susceptibility loci that influence the development
of RE-MDD. We completed a systematic survey of the human genome, conducted at
an average resolution of 10 cM, for the identification of simple sequence tandem
repeat polymorphisms (SSTRPs) that target susceptibility genes for RE-MDD by virtue
of linkage disequilibrium. The efficiency of our association study was enhanced
by genotyping pools of DNA from 100 adults with RE-MDD and 100 adult controls
who had no personal or family history of mental disorders. Both groups included
equal numbers of Caucasian men and women and were matched as closely as possible
for age and ethnicity. Allelic associations with RE-MDD were observed for 19 of
the 387 SSTRPs in the CHLC Human Screening Set/Weber Version 9. Sixteen of the
19 candidate susceptibility loci revealed significant allelic associations with
RE-MDD in men (n = 7) or women (n = 9), but not in both sexes. Evidence for both
risk and protective alleles was detected. Two of the candidate susceptibility
loci reside within several Mb of loci previously reported-megabases to be linked
to "comorbid alcoholism and depression" in families of individuals with
alcoholism and to a broadly defined affected phenotype that included recurrent
major depression in the families of patients with bipolar disorder. Although it
has been suggested that the genes that influence risk for MDD in the two sexes
may not be entirely the same, the results of our study suggest that sex specificity
of susceptibility loci for RE-MDD may be the rule rather than the exception. The
observed preponderance of sex-specific susceptibility loci for RE-MDD suggests
that there may be important differences in the molecular pathophysiology of RE-MDD
in men and women. Alternatively, our findings may reflect the existence of sex-specific
differences in the molecular mechanisms that determine resilience to endogenous
or environmental depressogenic stimuli." [Abstract] Wood
JG, Joyce PR, Miller AL, Mulder RT, Kennedy MA.
A polymorphism in
the dopamine beta-hydroxylase gene is associated with "paranoid ideation"
in patients with major depression.
Biol Psychiatry 2002
Mar 1;51(5):365-9
"BACKGROUND: Increased dopaminergic activity may play
a primary role in psychotic depression. Dopamine beta-hydroxylase (DbetaH) catalyses
the key step in biosynthesis of the neurotransmitter noradrenaline from dopamine,
and low DbetaH activity is a possible risk factor for developing psychotic depression.
An exon 2 polymorphism (DBH*444 g/a) of the DbetaH gene (DBH) is significantly
associated with both serum and cerebrospinal fluid levels of DbetaH. METHODS:
We determined the genotype of the DBH*444g/a polymorphism in a cohort of 164 patients
with major depression and examined the association of this polymorphism with paranoid
ideation, interpersonal sensitivity, and psychoticism on the Hopkins Symptom Checklist.
RESULTS: Patients who possessed the A allele were significantly more likely to
have higher scores for interpersonal sensitivity and paranoia than patients without
the A allele (p =.004 and p =.048, respectively), suggesting that this allele
may predispose patients to paranoia in major depression. In addition, we found
an association between prolactin levels in men and DBH*444 g/a genotype such that
homozygous G individuals displayed significantly higher levels than homozygous
A or heterozygote individuals. CONCLUSIONS: Depressed patients with the GG genotype
of DbetaH have lower scores for interpersonal sensitivity and paranoid ideation.
The GG genotype may be protective against the development of psychosis in the
presence of a major depressive episode." [Abstract] Cubells
JF, Price LH, Meyers BS, Anderson GM, Zabetian CP, Alexopoulos GS, Nelson JC,
Sanacora G, Kirwin P, Carpenter L, Malison RT, Gelernter J.
Genotype-controlled
analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major
depression.
Biol Psychiatry 2002 Mar 1;51(5):358-64
"BACKGROUND:
Plasma activity of dopamine beta-hydroxylase (DbetaH), the enzyme that converts
dopamine to norepinephrine, is reportedly lower in patients with unipolar major
depression with psychotic features (UDPF) than in those with nonpsychotic unipolar
major depression (UD). Plasma DbetaH is under genetic control by the structural
locus encoding DbetaH protein, DBH. This study tested the hypothesis that diagnosis-specific
allelic variation at DBH accounts for lower plasma DbetaH in UDPF. METHODS: Plasma
DbetaH activity was measured in samples from patients with UDPF (n = 33) and UD
(n = 45). Genotypes were determined at several functional DBH polymorphisms, including
C-1021T, a single nucleotide polymorphism (SNP) in the proximal 5' region that
associates with variation in plasma DbetaH activity. RESULTS: Mean plasma DbetaH
activity was significantly lower in UDPF than in UD. Genotyping at DBH did not
reveal genetic associations distinguishing UDPF from UD. A two-way analysis of
variance showed significant effects of genotype and diagnostic group but no significant
interaction. CONCLUSIONS: Although the effects of the diagnosis of UDPF, and of
DBH allele status, on plasma DbetaH activity were replicated, the lower plasma
DbetaH in patients with UDPF was not accounted for by DBH genotype. Several explanations
for this result are possible. First, other variants at DBH, or at other loci,
could account for the findings. Second, nongenetic factors could account for the
differences in plasma DbetaH. In this regard, we hypothesize that abnormal regulation
of hypothalamic-pituitary-adrenal function in UDPF lowers expression of DbetaH
protein, which could in turn alter the ratio of dopamine and norepinephrine in
noradrenergic neurons, thereby promoting development of psychotic symptoms."
[Abstract] Holmans
P, Zubenko GS, Crowe RR, DePaulo JR Jr, Scheftner WA, Weissman MM, Zubenko WN,
Boutelle S, Murphy-Eberenz K, MacKinnon D, McInnis MG, Marta DH, Adams P, Knowles
JA, Gladis M, Thomas J, Chellis J, Miller E, Levinson DF.
Genomewide
Significant Linkage to Recurrent, Early-Onset Major Depressive Disorder on Chromosome
15q.
Am J Hum Genet. 2004 Jun;74(6):1154-67.
"A
genome scan was performed on the first phase sample of the Genetics of Recurrent
Early-Onset Depression (GenRED) project. The sample consisted of 297 informative
families containing 415 independent affected sibling pairs (ASPs), or, counting
all possible pairs, 685 informative affected relative pairs (555 ASPs and 130
other pair types). Affected cases had recurrent major depressive disorder (MDD)
with onset before age 31 years for probands or age 41 years for other affected
relatives; the mean age at onset was 18.5 years, and the mean number of depressive
episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite
markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele
sharing in all possible affected relative pairs with the use of the Z(lr) statistic
computed by the ALLEGRO program. A secondary logistic regression analysis considered
the effect of the sex of the pair as a covariate. Genomewide significant linkage
was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical
genomewide P=.023). The linkage was not sex specific. No other suggestive or significant
results were observed in the primary analysis. The secondary analysis produced
three regions of suggestive linkage, but these results should be interpreted cautiously
because they depended primarily on the small subsample of 42 male-male pairs.
Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility
to MDD." [Abstract]
Abkevich
V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC, Plenk AM, Lowry MR, Richards
RL, Carter C, Frech GC, Stone S, Rowe K, Chau CA, Cortado K, Hunt A, Luce K, O'Neil
G, Poarch J, Potter J, Poulsen GH, Saxton H, Bernat-Sestak M, Thompson V, Gutin
A, Skolnick MH, Shattuck D, Cannon-Albright L.
Predisposition locus
for major depression at chromosome 12q22-12q23.2.
Am J Hum
Genet. 2003 Dec;73(6):1271-81. Epub 2003 Nov 05.
"Major depression disorder
is a common psychiatric disease with a major economic impact on society. In many
cases, no effective treatment is available. The etiology of major depression is
complex, but it is clear that the disease is, to a large extent, determined genetically,
especially among individuals with a familial history of major depression, presumably
through the involvement of multiple predisposition genes in addition to an environmental
component. As a first step toward identification of chromosomal loci contributing
to genetic predisposition to major depression, we have conducted a genomewide
scan by using 628 microsatellite markers on 1,890 individuals from 110 Utah pedigrees
with a strong family history of major depression. We identified significant linkage
to major depression in males at marker D12S1300 (multipoint heterogeneity LOD
score 4.6; P=.00003 after adjustment for multiple testing). With additional markers,
the linkage evidence became highly significant, with the multipoint heterogeneity
LOD score at marker D12S1706 increasing to 6.1 (P=.0000007 after adjustment for
multiple testing). This study confirms the presence of one or more genes involved
in psychiatric diseases on the q arm of chromosome 12 and provides strong evidence
for the existence of a sex-specific predisposition gene to major depression at
12q22-q23.2." [Abstract] Blackwood
DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ.
Schizophrenia
and affective disorders--cosegregation with a translocation at chromosome 1q42
that directly disrupts brain-expressed genes: clinical and P300 findings in a
family.
Am J Hum Genet 2001 Aug;69(2):428-33
"A
family with a (1;11)(q42;q14.3) translocation significantly linked to a clinical
phenotype that includes schizophrenia and affective disorders is described. This
translocation generates a LOD score of 3.6 when the disease phenotype is restricted
to schizophrenia, of 4.5 when the disease phenotype is restricted to affective
disorders, of 7.1 when relatives with recurrent major depression, with bipolar
disorder, or with schizophrenia are all classed as affected. This evidence for
linkage is among the strongest reported for a psychiatric disorder. Family members
showed no distinctive features by which the psychiatric phenotype could be distinguished
from unrelated cases of either schizophrenia or affective disorders, and no physical,
neurological, or dysmorphic conditions co-occurred with psychiatric symptoms.
Translocation carriers and noncarriers had the same mean intelligence quotient.
Translocation carriers were similar to subjects with schizophrenia and different
from noncarriers and controls, in showing a significant reduction in the amplitude
of the P300 event-related potential (ERP). Furthermore, P300 amplitude reduction
and latency prolongation were measured in some carriers of the translocation who
had no psychiatric symptoms-a pattern found in other families with multiple members
with schizophrenia, in which amplitude of and latency of P300 appear to be trait
markers of risk. The results of karyotypic, clinical, and ERP investigations of
this family suggest that the recently described genes DISC1 and DISC2, which are
directly disrupted by the breakpoint on chromosome 1, may have a role in the development
of a disease phenotype that includes schizophrenia as well as unipolar and bipolar
affective disorders." [Abstract] Covault
J, Pettinati H, Moak D, Mueller T, Kranzler HR.
Association of a
long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with
enhanced niacin-induced dermal erythema.
Am J Med Genet.
2004 May 15;127B(1):42-7.
"Hypotheses about relationships between changes
in membrane lipids and mental illness have focused primarily on three long-chain
polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA),
and docosahexaenoic acid (DHA). Membrane deficiencies of these fatty acids have
been reported in schizophrenia (AA, EPA, and DHA) and in depression (EPA and DHA).
Long-chain fatty acid-CoA ligase type 4 (FACL4; MIM 300157) is a key enzyme involved
in the metabolism of AA, EPA, and DHA. FACL4 selectively esterifies these fatty
acids with co-enzyme A, forming acyl-co-A, which can then be incorporated into
membrane phospholipid. We used niacin-induced dermal erythema as one index of
AA metabolism to identify a common C to T single nucleotide polymorphism (SNP)
in the first intron of the FACL4 gene (Xq22.3), which is associated with enhanced
dermal erythema in both schizophrenia and control subjects. Male subjects with
the T0 genotype showed greater dermal erythema following topical application of
methylnicotinate, suggesting that this polymorphism may be in linkage disequilibrium
with a functional polymorphism of the FACL4 gene that modulates re-sequestration
of agonist-released free AA. We also examined the allele frequency of this polymorphism
in 555 European-Americans (EA), including 229 control subjects, 198 subjects with
major depression, 58 with schizophrenia or schizoaffective disorder, and 70 with
alcohol dependence without co-morbid psychiatric illness. We observed a significant
excess of the T allele in subjects with major depression, as compared with controls
(49% vs. 38%; P = 0.003) and a non-significant excess of the T allele in schizophrenia
(44%; P = 0.29). The allele frequency for subjects with alcohol dependence did
not differ from controls." [Abstract] Philibert
R, Caspers K, Langbehn D, Troughton EP, Yucuis R, Sandhu HK, Cadoret RJ.
The
association of a HOPA polymorphism with major depression and phobia.
Compr
Psychiatry 2002 Sep-Oct;43(5):404-10
"Thyroid hormone has a prominent
role in the development and homeostasis of the central nervous system (CNS). Consequently,
genes participating in thyroid hormone receptor (THR)-mediated signal transduction
are prime candidates for neuropsychiatric illness susceptibility factors. Previously,
we have associated exonic polymorphisms in a Xq13 thyroid receptor coactivator
named HOPA with a modest increase in vulnerability to a broad spectrum of neuropsychiatric
illness, including depression, psychosis, and hypothyroidism. In order to test
and extend these findings, we have now examined the relationship between HOPA
polymorphisms and neuropsychiatric illness in a cohort of Iowa adoptees. Consistent
with our prior findings, HOPA polymorphisms were associated with an increased
risk for major depression. There was suggestive evidence that the increased psychiatric
morbidity in these subjects could represent epistasis, e.g., an interaction between
the HOPA variant and a genetic diathesis for another psychiatric condition such
as biologic parent antisocial behavior. Information about biologic parent behavior
and the adoptive home environment was used to determine depressive symptoms attributable
to gene-environment interaction. HOPA variant subjects continued to show significant
differences in depressive symptoms when controlling for gene-environment interaction.
Finally, because obesity is associated with hypothyroidism and HOPA polymorphisms
are associated with hypothyroidism, we analyzed weight with respect to HOPA allele
status. We found that that HOPA polymorphisms were associated with increased risk
for obesity (P <.001). In summary, we conclude that HOPA polymorphisms may
be a moderate risk factor for increased susceptibility to a broad spectrum of
neuropsychiatric illness and hypothesize that the type of illness manifested might
be related to a separate genetic diathesis." [Abstract] Ryu
SH, Lee SH, Lee HJ, Cha JH, Ham BJ, Han CS, Choi MJ, Lee MS.
Association
between Norepinephrine Transporter Gene Polymorphism and Major Depression.
Neuropsychobiology.
2004;49(4):174-7.
"Noradrenergic and serotonergic abnormalities have long
been implicated in patients with major depression. The novel selective norepinephrine
reuptake inhibitor reboxetine has been shown to be at least as effective as imipramine,
desipramine and fluoxetine in the treatment of major depression. It is suggested
that the dysfunction of the norepinephrine transporter (NET) may be related to
major depression. Although the transcriptional activity related to the NET gene
expression is little known, it may be a good candidate gene for major depression.
Therefore, we investigated whether the T-182C polymorphism of the NET gene is
associated with major depression in a Korean sample of 112 major depression patients
compared with 136 healthy controls. We found a significantly lower frequency in
TT genotype in patients with major depression than in normal controls when the
genotypes of T-182C polymorphism were classified into two groups: TT group versus
TC + CC group (p = 0.019). This result suggests that the T-182C polymorphism in
the NET gene might be associated with 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 [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
"Our results suggest that the investigated polymorphisms
are not major susceptibility factors in the etiology of major depression."
[Abstract] |
van West D, Del-Favero J, Aulchenko Y, Oswald P,
Souery D, Forsgren T, Sluijs S, Bel-Kacem S, Adolfsson R, Mendlewicz J, Van Duijn
C, Deboutte D, Van Broeckhoven C, Claes S.
A major SNP haplotype
of the arginine vasopressin 1B receptor protects against recurrent major depression.
Mol
Psychiatry. 2004 Mar;9(3):287-92.
"Increasing amounts of data suggest
that affective disorders might be related to dysregulation of the hypothalamic-pituitary-adrenal
(HPA) axis, one of the stress-response systems. Arginine vasopressin (AVP) influences
several symptoms, relevant to affective disorders, notable memory processes, pain
sensitivity, synchronization of biological rhythms and the timing and quality
of REM sleep. We examined whether genetic variations in the AVP receptor 1b gene
(AVPR1b) could be associated with increased susceptibility to affective disorders
using a gene-based association analysis of single-nucleotide polymorphisms (SNPs).
Five SNPs were identified in AVPR1b and genotyped in two well-diagnosed samples
of patients with recurrent major depression and matched controls. In the Swedish
sample, we observed significant allele (P=0.02) and genotype (P=0.01) association
with SNP AVPR1b-s3, and in the Belgian sample, a borderline significant association
with SNP AVPR1b-s5 (P=0.04). In both patient-control samples, the haplotype defined
by alleles A-T-C-A-G for the AVPR1b-s SNPs s1-s2-s3-s4-s5 was significantly over-represented
in controls compared to patients. Our data support a protective effect of this
major haplotype for recurrent major depression." [Abstract] Claes
S, Villafuerte S, Forsgren T, Sluijs S, Del-Favero J, Adolfsson R, Van Broeckhoven
C.
The corticotropin-releasing hormone binding protein is associated
with major depression in a population from Northern Sweden.
Biol
Psychiatry. 2003 Nov 1;54(9):867-72.
"BACKGROUND: Recent research suggests
that central corticotropin releasing hormone hyperdrive is an important neurobiological
risk factor for developing major depression. The availability of free corticotropin
releasing hormone in the central nervous system is tightly regulated by the expression
of corticotropin releasing hormone binding protein. Therefore, the gene encoding
for corticotropin releasing hormone binding protein is a functional candidate
gene for major depression. METHODS: We present a systematic study of single nucleotide
polymorphisms in the corticotropin releasing hormone binding protein gene and
their role in the liability for major depression. Seven single nucleotide polymorphisms
were genotyped in a well-diagnosed sample of 89 patients with recurrent major
depressions and matched controls. RESULTS: Two single nucleotide polymorphisms
within the corticotropin releasing hormone binding protein gene were significantly
associated with the disease (p <.05). An expectation-maximization algorithm
estimated a specific haplotype to have a frequency of 53% in patients and 35%
in controls (p <.001). CONCLUSIONS: The corticotropin releasing hormone binding
protein gene is likely to be involved in the genetic vulnerability for major depression."
[Abstract]
Heiman GA, Ottman R, Saunders-Pullman RJ, Ozelius LJ, Risch NJ, Bressman SB
Increased risk for recurrent major depression in DYT1 dystonia mutation carriers.
Neurology. 2004 Aug 24;63(4):631-7.
BACKGROUND: Prior studies suggest that dystonia is comorbid with affective disorders. This comorbidity could be a reaction to a chronic debilitating disorder or expression of a predisposing gene. The authors took advantage of the identification of a gene for dystonia, DYT1, to test these alternative explanations. METHODS: The authors administered a standardized psychiatric interview to members of families with an identified DYT1 mutation. The authors classified family members into three groups: mutation carriers with dystonia (manifesting carriers; n = 96), mutation carriers without dystonia (non-manifesting carriers; n = 60), and noncarriers (n = 65). RESULTS: The risk for recurrent major depressive disorder was increased in both non-manifesting carriers (RR = 4.95, CI = 1.72 to 14.29) and manifesting carriers (RR = 3.62, CI = 1.00 to 10.53) compared with noncarriers. Mutation carriers also had earlier age at onset of recurrent major depressive disorder than noncarriers. The severity of motor signs was not associated with the likelihood of recurrent depression. Mutation carriers did not have an increased risk for other affective disorders, such as single major depression or bipolar disorder. CONCLUSIONS: Early-onset recurrent major depression is associated with the DYT1 GAG mutation and this association is independent of motor manifestations of dystonia. These findings suggest that early-onset recurrent depression is a clinical expression of the DYT1 gene mutation. [Abstract]
Koido K, Kks S, Nikopensius T, Maron E, Altme S, Heinaste E, Vabrit K, Tammekivi V, Hallast P, Kurg A, Shlik J, Vasar V, Metspalu A, Vasar E
Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders.
Int J Neuropsychopharmacol. 2004 10 11;1-10.
Wolfram syndrome gene (WFS1) has been suggested to have a role in the susceptibility for mood disorders. A 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers has been suggested. In this study we tested the hypothesis that the WFS1 gene is related to the risk for mood disorders. We analysed 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects. Patients were further stratified according to their comorbidity with anxiety disorders. We applied arrayed primer extension (APEX)-based genotyping technology followed by association and haplotype analysis. Five SNPs in the WFS1 gene were associated with major depressive disorder, and three SNPs with bipolar disorder. Haplotype analysis revealed a common GTA haplotype, formed by SNPs 684CG, 1185CT and 1832GA, conferring risk for affective disorders. Specifically, for major depression the GTA haplotype has an OR of 1.59 (p=0.01) and for bipolar disorder an OR of 1.89 (p=0.03). These results support the hypothesis that the WFS1 gene is involved in the genetic predisposition for mood disorders. [Abstract]
Serretti
A, Lilli R, Lorenzi C, Lattuada E, Smeraldi E.
DRD4 exon 3 variants
associated with delusional symptomatology in major psychoses: a study on 2,011
affected subjects.
Am J Med Genet 2001 Apr 8;105(3):283-90
"We
previously reported an association of DRD4 exon3 long allele variants with delusional
symptomatology independently from diagnoses. The aim of this investigation was
to study DRD4 in major psychoses and to test the association in a larger sample.
We studied 2,011 inpatients affected by bipolar disorder (n = 811), major depressive
disorder (n = 635), schizophrenia (n = 419), delusional disorder (n = 104), psychotic
disorder not otherwise specified (n = 42), and 601 healthy controls. A subsample
of 1,264 patients were evaluated using the OPCRIT checklist and differences of
symptomatology factor scores among genetic variants were assessed using one-way
analysis of variance (ANOVA). DRD4 allele and genotype frequencies in bipolars,
schizophrenics, delusionals, and psychotic NOS were not significantly different
from controls; major depressives showed a trend toward an excess of DRD4*Short
and DRD4*Short/Short variants versus controls. The ANOVA on factor scores in the
whole subsample of 1,264 subjects showed a significant difference on delusion
factor in allele analysis (P = 0.007), and in genotype one (P = 0.018), with DRD4*Long
containing variants associated with severe symptomatology. The analysis in the
replication subjects only (n = 803) showed a trend in the same direction, though
not reaching the significance level. This analysis in an enlarged sample suggests
that DRD4*Long alleles exert a small but significant influence on the delusional
symptomatology in subjects affected by major psychoses." [Abstract]
Serretti
A, Lilli R, Di Bella D, Bertelli S, Nobile M, Novelli E, Catalano M, Smeraldi
E.
Dopamine receptor D4 gene is not associated with major psychoses.
Am
J Med Genet 1999 Oct 15;88(5):486-91
"We previously reported an association
between dopamine receptor D4 (DRD4) gene exon 1 variants and delusional disorder.
The aim of this investigation was to study the DRD4 gene exon 1 and 3 variants
in schizophrenia, delusional, bipolar, and unipolar disorders. We studied 651
inpatients affected by schizophrenia (n = 229), delusional (n = 86), bipolar (n
= 210), and unipolar (n = 126) disorders (DSM III-R) and 471 healthy controls;
these were typed for DRD4 variants at the first and third exon using polymerase
chain reaction techniques. DRD4 variants were not associated with schizophrenic
and delusional subjects even when possible confounders like gender and onset were
considered. A marginal association between DRD4 exon 3 variants with unipolar
(excess of DRD4*2/4, p = 0.004) and bipolar (excess of DRD4*2/4, p = 0.001) disorders
was observed, both associations drop to insignificance when corrected for multiple
testing. Our results exclude that coding variants of the DRD4 exon 1 and 3 may
play a major role in conferring susceptibility to major psychoses; moreover, we
could not replicate the association of DRD4 exon 1 variant with delusional disorder."
[Abstract] Serretti
A, Macciardi F, Cusin C, Lattuada E, Lilli R, Smeraldi E.
Dopamine
receptor D4 gene is associated with delusional symptomatology in mood disorders.
Psychiatry
Res 1998 Aug 17;80(2):129-36
"Disturbances of the dopaminergic neurotransmitter
system have been implicated in the pathogenesis of depressive symptoms. Many studies
have, however, failed to detect any association between genetic markers for the
dopamine system and mood disorders. A possible reason for this may lie in the
definition of phenotype, which is traditionally based on psychiatric diagnosis.
In this study, we investigated the possibility that functional variants of the
dopamine D4 receptor (DRD4) gene might be associated with depressive symptomatology
in a sample of mood disorder subjects. Seventy-nine inpatients affected by bipolar
(n=37) and major depressive (n=42) disorder (DSM-IV) were assessed at admission
by the Hamilton Depression Rating Scale and were typed for DRD4 variants at the
third exon using polymerase chain reaction (PCR) techniques. DRD4 was associated
with delusional symptoms (F=5.56; d.f.=2,145; P=0.005), with DRD4*7 exhibiting
higher scores when compared to DRD4*4 (P=0.006) variants. Polarity of mood disorder
did not influence results significantly. The findings are in accordance with our
previous report of an association of the DRD4 gene with delusional symptomatology
of major psychoses. DRD4*7 should, therefore, be considered a liability factor
for delusional symptoms in mood disorders." [Abstract] Serretti
A, Cusin C, Lattuada E, Lilli R, Lorenzi C, Di Bella D, Catalano M, Smeraldi E.
No
interaction between serotonin transporter gene and dopamine receptor D4 gene in
symptomatology of major psychoses.
Am J Med Genet 1999 Oct
15;88(5):481-5
"Previously, we reported an association of the dopamine
receptor D4 (DRD4) gene with delusional symptomatology of major psychoses. However,
DRD4 variants accounted for only 2% of the phenotypic variance, indicating that
contributions from other genes were probable. The serotonin transporter gene is
a primary candidate in major psychoses, and a functional polymorphism in the upstream
regulatory region of the serotonin transporter gene (5-HTTLPR) has recently been
reported to be associated with a number of psychopathological conditions. In the
present study we investigated the original cohort of subjects to evaluate the
5-HTTLPR possible influence on the psychopathology of major psychoses in interaction
with DRD4. Four hundred and sixty-one inpatients affected by major psychoses were
assessed by the Operational Criteria Checklist for Psychotic Illness (OPCRIT)
and were also typed for the 5-HTTLPR and DRD4 variants using polymerase chain
reaction techniques. Mania, depression, delusion, and disorganization were the
four symptomatologic factors used as phenotype definition. 5-HTTLPR variants did
not significantly influence the previously reported association of DRD4 with delusional
symptoms. No interaction was observed on the other symptom factors. The serotonin
transporter gene does not, therefore, interact with DRD4 in determining the symptomatology
of major psychoses." [Abstract] Persson
ML, Geijer T, Wasserman D, Rockah R, Frisch A, Michaelovsky E, Jonsson EG, Apter
A, Weizman A.
Lack of association between suicide attempt and a polymorphism
at the dopamine receptor D4 locus.
Psychiatr Genet 1999
Jun;9(2):97-100 |
