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
Neuroreport 2000 Jun 26;11(9):1893-7
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]
HJ, Cha JH, Ham BJ, Han CS, Kim YK, Lee SH, Ryu SH, Kang RH, Choi MJ, Lee MS.
between a G-protein beta3 subunit gene polymorphism and the symptomatology and
treatment responses of major depressive disorders.
"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.
antidepressant activity is influenced by G beta 3 variants.
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]
MS, Artz M, Siffert W, Schedlowski M.
G protein beta3 subunit 825T
allele is associated with depression in young, healthy subjects.
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]
PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR, Kennedy MA.
antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and
G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline.
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."
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?
"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
Association study of C825T polymorphism of the G-protein b3 subunit
gene with schizophrenia and mood disorders.
J Neural Transm
"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]
CN, Tsai SJ, Hong CJ.
Association analysis of a functional G protein
beta3 subunit gene polymorphism (C825T) in mood disorders.
"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
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.
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,
Am J Med Genet 2002 Dec 8;114(8):980-7
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."
GS, Maher B, Hughes HB 3rd, Zubenko WN, Stiffler JS, Kaplan BB, Marazita ML.
linkage survey for genetic loci that influence the development of depressive disorders
in families with recurrent, early-onset, major depression.
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]
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]
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
"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."
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]
DE, Wu S, Rostamkhani M, McGue M, Iacono WG, MacMurray JP.
of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in
Am J Med Genet 2002 Jul 8;114(5):527-9
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]
GS, Hughes III HB, Stiffler JS, Zubenko WN, Kaplan BB.
a likely susceptibility locus for recurrent, early-onset, major depression in
Mol Psychiatry 2002;7(5):460-7
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]
R, Caspers K, Langbehn D, Troughton EP, Yucuis R, Sandhu HK, Cadoret RJ.
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.
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]
GS, Hughes HB, Stiffler JS, Zubenko WN, Kaplan BB.
for susceptibility loci for recurrent, early-onset major depression: results at
Am J Med Genet 2002 May 8;114(4):413-22
(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]
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
"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]
JF, Price LH, Meyers BS, Anderson GM, Zabetian CP, Alexopoulos GS, Nelson JC,
Sanacora G, Kirwin P, Carpenter L, Malison RT, Gelernter J.
analysis of plasma dopamine beta-hydroxylase activity in psychotic unipolar major
Biol Psychiatry 2002 Mar 1;51(5):358-64
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."
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.
Significant Linkage to Recurrent, Early-Onset Major Depressive Disorder on Chromosome
Am J Hum Genet. 2004 Jun;74(6):1154-67.
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]
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.
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
DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ.
and affective disorders--cosegregation with a translocation at chromosome 1q42
that directly disrupts brain-expressed genes: clinical and P300 findings in a
Am J Hum Genet 2001 Aug;69(2):428-33
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]
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]
R, Caspers K, Langbehn D, Troughton EP, Yucuis R, Sandhu HK, Cadoret RJ.
association of a HOPA polymorphism with major depression and phobia.
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]
SH, Lee SH, Lee HJ, Cha JH, Ham BJ, Han CS, Choi MJ, Lee MS.
between Norepinephrine Transporter Gene Polymorphism and Major Depression.
"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]
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 [Abstract]
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.
"Our results suggest that the investigated polymorphisms
are not major susceptibility factors in the etiology of major depression."
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.
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]
S, Villafuerte S, Forsgren T, Sluijs S, Del-Favero J, Adolfsson R, Van Broeckhoven
The corticotropin-releasing hormone binding protein is associated
with major depression in a population from Northern Sweden.
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."
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]
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
Am J Med Genet 2001 Apr 8;105(3):283-90
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]
A, Lilli R, Di Bella D, Bertelli S, Nobile M, Novelli E, Catalano M, Smeraldi
Dopamine receptor D4 gene is not associated with major psychoses.
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."
A, Macciardi F, Cusin C, Lattuada E, Lilli R, Smeraldi E.
receptor D4 gene is associated with delusional symptomatology in mood disorders.
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]
A, Cusin C, Lattuada E, Lilli R, Lorenzi C, Di Bella D, Catalano M, Smeraldi E.
interaction between serotonin transporter gene and dopamine receptor D4 gene in
symptomatology of major psychoses.
Am J Med Genet 1999 Oct
"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]
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
K, Zubenko GS, Giles DE, Frank E, Kupfer DJ, Kaplan BB.
association analysis of chromosomal regions containing genes related to neuroendocrine
or serotonin function in families with early-onset, recurrent major depression.
J Med Genet 1998 Sep 7;81(5):443-9
"Recurrent unipolar depression with
an early age of onset is a severe form of unipolar depression that has both genetic
and environmental components. We genotyped the members of 16 families identified
by probands with early onset (< or = 25 years), recurrent unipolar, major depression
for 38 simple sequence tandem repeat polymorphisms (SSTRPs) from chromosomal regions
containing 12 genes involved in neuroendocrine or serotonergic functioning. Pairwise
linkage analysis was performed with the software package FASTLINK. The affected
phenotype was defined four ways, and both dominant and recessive models of depression
were analyzed. Seven SSTRPs showed lod scores > 1.00 at theta values between
0.10-0.20. The members of an additional 18 families were genotyped for these seven
SSTRPs, and the complete sample of 34 families was evaluated using lod score analysis,
affected pedigree member linkage analysis, and within-family association analysis.
Evidence for linkage between D11S929 and affective illness remained positive,
necessitating the analysis of four additional SSTRPs within 3 cM of D11S929. After
all confirmatory analyses were completed, no evidence suggestive of linkage remained
between any of the 38 SSTRPs and the affected phenotypes." [Abstract]
Gutiérrez B, Arias B, Gastó C, Catalán R, Papiol S, Pintor L, Fañanás L
Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders.
Psychiatr Genet. 2004 Dec;14(4):203-8.
Monoamine oxidase A (MAOA) has been suggested to be involved in human behaviour and physiology due to its key role in the metabolism of several different biological amines including the neurotransmitters serotonin, norepinephrin and dopamine.Recently, a 30 bp repeat in the MAOA gene promoter (uMAOA) has been demonstrated to be polymorphic and to affect transcriptional activity.In the context of an association case-control study design, we analysed the uMAOA polymorphism in 389 unrelated patients affected by severe mood disorders (88 bipolar subjects and 301 major depressive individuals) and in 156 controls. No association was found between the uMAOA locus and bipolar disorder or major depression. However, an increase of high-activity uMAOA alleles was found in major depression female patients presenting a seasonal pattern (chi2=3.013, P=0.05) or psychotic symptoms in their episodes (chi2=2.679, P=0.07). In female bipolar disorder patients, long alleles were associated with longest times of admission (F=4.604, P=0.037). A trend for association with seasonal pattern was also defined in this group (data not corrected for multiple testing). Our results suggest that MAOA gene variation may modulate the expression of some clinical aspects of severe mood disorders, especially in females, and support the existence of a genetic and aetiologic heterogeneity underlying the diagnoses of bipolar disorder and major depression. [Abstract]
TG, Muller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt
H, Grassle M, Papassotiropoulos A, Heun R, Nothen MM, Maier W, Lesch KP, Rietschel
Association between a functional polymorphism in the monoamine
oxidase A gene promoter and major depressive disorder.
J Med Genet 2000 Dec 4;96(6):801-3
"Various polymorphisms of the X-chromosomal
monoamine oxidase A (MAO-A) gene were investigated for association with affective
disorders. However, none of the studied variants could consistently be associated
with either major depressive or bipolar affective disorder. Recently, a positive
association between panic disorder and a novel functional repeat polymorphism
in the MAO-A gene promoter, with the longer alleles being more active, was reported.
Since monoaminergic neurotransmission is supposed to play an important role in
affective disorders, we investigated a potential association of this polymorphism
with major depressive illness in a sample of 146 unrelated patients of German
descent and a control group of 101 individuals with a negative life history for
affective disorders. Similarly to the recent findings in panic disorder, we observed
a significantly increased frequency of genotypes containing only long alleles
in female patients with recurrent major depression in comparison with age- and
sex-matched controls. Thus, our data suggest that an excess of high-activity MAO-A
gene promoter alleles resulting in an elevated MAO-A activity is a risk factor
for major depressive disorder in females." [Abstract]
Du L, Bakish D, Ravindran A, Hrdina PD
MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males.
Neuroreport. 2004 Sep 15;15(13):2097-101.
We investigated whether the genetic variants of the MAO-A gene were associated with major depression and/or the clusters of depressive symptoms. The EcoRV and the uVNTR polymorphisms were studied in a population of 191 patients with major depression and 233 control subjects. The EcoRV polymorphism was found to be associated with depression in males but not in females. Haplotype analysis revealed that one of the haplotypes (EcoRV2-uVNTR1) was significantly more frequent among male patients than male controls. Among the HAMD symptom clusters, insomnia scores were significantly higher in male patients carrying allele 2 of the EcoRV polymorphism. These data suggest that the EcoRV and uVNTR polymorphisms may be involved in the pathogenesis of major depression and associated with insomnia in depressed patients. [Abstract]
A, Rujescu D, Szegedi A, Giegling I, Singer P, Moller HJ, Dahmen N.
of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder
or major depression.
Am J Med Genet 2003 Feb 15;117B(1):1-6
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."
Kunugi H, Ishida S, Kato T, Tatsumi M, Sakai T, Hattori
M, Hirose T, Nanko S.
A functional polymorphism in the promoter region
of monoamine oxidase-A gene and mood disorders.
"A polymorphism of a variable number tandem repeat
(VNTR), that was recently found in the promoter region of the monoamine oxidase-A
(MAOA) gene, was shown to be associated with its transcriptional activity. This
study examined whether this functional polymorphism of the MAOA gene is associated
with the risk of developing mood disorders in a Japanese sample of 161 patients
with bipolar disorder, 98 with unipolar depression, and 258 controls. There was
no significant genotypic or allelic association, suggesting that the functional
VNTR polymorphism in the MAOA gene is unlikely to play a major role in the pathogenesis
of bipolar disorder or unipolar depression. Furthermore, we found no association
between the polymorphism and a history of suicide attempt." [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]
Qian Y, Lin S, Jiang S, Jiang K, Wu X, Tang
G, Wang D.
Studies of the DXS7 polymorphism at the MAO loci in unipolar
Am J Med Genet 1999 Dec 15;88(6):598-600
the fact that DXS7 polymorphism is closely related to monoamine oxidase (MAO)
genes and MAO inhibitors are widely used in the treatment of unipolar depression,
it is of particular interest to study the relationship between the DXS7 polymorphism
and unipolar depression. Thus, this study examined the possible association between
DXS7 polymorphism and unipolar depression in 66 cases versus 85 controls from
Shanghai. Polymerase chain reaction and amplification fragment length polymorphism
techniques were used for genotyping of the DXS7 locus in this study. Four alleles
at the DXS7 locus were detected with length generated by polymerase chain reaction
amplification ranging from 157 to 167 bp. Comparison of allele frequency in the
DXS7 locus showed no difference between unipolar depression cases and normal controls
in the total population set. When subclassified by age, a significant difference
of allele frequency distribution was observed between early onset (before age
40) and late onset (after age 40) patients. The frequency of the 157-bp allele
was decreased, whereas the frequency of the 165 allele was increased in late onset
patients (0.3810 for the 157-bp allele and 0.5238 for the 165-bp allele) compared
with that of early onset patients (0.6304 for the 157-bp allele and 0. 3261 for
the 165-bp allele). There was also a difference of allele frequency between patients
and normal controls with age over 40 years. The frequency of 165-bp allele increased
significantly in late onset patients (0.5238) compared with that of controls within
the same age range (0.3454). Association studies suggested that in the population
with age over 40 years, presence of the 165-bp allele of DXS7 locus was significantly
associated with unipolar depression (relative risk = 2.08, P < 0.05), whereas
in the total population set, this association did not exist." [Abstract]
Serretti A, Cristina S, Lilli R, Cusin C, Lattuada
E, Lorenzi C, Corradi B, Grieco G, Costa A, Santorelli F, Barale F, Nappi G, Smeraldi
Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4
polymorphisms in mood disorders.
Am J Med Genet 2002 May
"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]
A, Macciardi F, Cusin C, Verga M, Pedrini S, Smeraldi E.
hydroxylase gene in linkage disequilibrium with mood disorders.
Psychiatry 1998 Mar;3(2):169-74
"We studied tyrosine hydroxylase (TH)
gene variants in mood disorders using linkage disequilibrium techniques. One hundred
and forty-five inpatients affected by bipolar (n = 88) and unipolar (n = 57) disorders,
and 84 healthy controls, were typed for TH variants using polymerase chain reaction
(PCR) amplification. TH was associated with mood disorder, with all affected subjects
presenting an excess of TH*2 allele (chi 2 = 8.30, d.f. = 1; P = 0.004) and lack
of the TH*1 allele (chi 2 = 6.90, d.f. = 1, P = 0.009). Linkage disequilibrium
analyses confirmed the association. Our results suggest a moderate linkage disequilibrium
of TH variants with mood disorders." [Abstract]
Furlong RA, Rubinsztein JS, Ho L, Walsh C, Coleman
TA, Muir WJ, Paykel ES, Blackwood DH, Rubinsztein DC.
metaanalysis of two polymorphisms within the tyrosine hydroxylase gene in bipolar
and unipolar affective disorders.
Am J Med Genet 1999 Feb
"Tyrosine hydroxylase (TH) is the rate-limiting enzyme in
the synthesis of dopamine and noradrenaline. While positive associations between
TH and bipolar affective disorder have been found in several studies, many studies
have failed to reproduce these results. In order to clarify this situation, association
studies of bipolar and unipolar affective disorder groups and metaanalyses of
published data on the TH tetranucleotide repeat polymorphism were done. The association
studies used the TH tetranucleotide repeat polymorphism in intron 1 and a PstI
polymorphism at the 3' end of the gene. The study comprised 124 unrelated bipolar
patients, 126 unipolar patients, and 242 controls. There was no significant association
of either bipolar or unipolar affective disorder with the TH tetranucleotide repeat
polymorphism. However, a weak association (chi2 = 3.946, 1 df, P = 0.047; odds
ratio, allele 2 vs. allele 1 = 0.71 (95% CI, 0.51-0.996)) was observed in the
unipolar sample with the TH-PstI polymorphism. Three metaanalyses of published
data on the TH tetranucleotide repeat polymorphism in major affective disorder
were performed: bipolar I + II vs. control using 583 cases and 745 controls; unipolar
vs. control using 204 cases and 359 controls; and bipolar + unipolar vs. control
using 846 cases and 823 controls. In each analysis there was no association of
the TH tetranucleotide repeat polymorphism and affective disorder. These results
do not support the tyrosine hydroxylase gene having a major role in the etiology
of bipolar affective disorder. However, our data suggest that this locus should
be examined in larger samples of unipolar affective disorder." [Abstract]
L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Raeymaekers P, Van Broeckhoven
Analysis of the tyrosine hydroxylase and dopamine D4 receptor
genes in a Croatian sample of bipolar I and unipolar patients.
J Med Genet 1997 Apr 18;74(2):176-8
"We selected 83 patients with bipolar
disorder type I or unipolar recurrent major depression and 71 healthy controls
for genetic analysis of the tyrosine hydroxylase and the dopamine D4 receptor
gene. No significant association was found between bipolar disorder type I and
unipolar recurrent major depression and the polymorphisms located near these genes.
Therefore, the hypothesis that the tyrosine hydroxylase and the dopamine D4 receptor
genes may be involved in the etiology of bipolar disorder and unipolar recurrent
major depression is not supported in our study." [Abstract]
S, Xiang F, Sydow O, Jonsson EG, Sedvall GC, Anvret M, Olson L.
Identification of four novel polymorphisms in the calcitonin/alpha-CGRP (CALCA)
gene and an investigation of their possible associations with Parkinson disease,
schizophrenia, and manic depression.
Hum Mutat 2001 May;17(5):435-6
"We identified novel polymorphisms in the calcitonin/CGRPalpha (CALCA) gene
by direct sequencing of genomic DNA and subsequent genotyping by RFLP (restriction
fragment length polymorphism) detection and investigated association with neurological
or psychiatric disease. Four novel polymorphic alleles were found: two (g.979G>A
and g.4218T>C) represented single nucleotide polymorphisms (SNPs), one consisted
of two coupled SNPs in close vicinity to each other (g.1210T>C and g.1214C>G),
and one was an intronic 16-bp microdeletion (2919-2934del16). One of the SNPs
(g.4218T>C) causes a non-synonymous amino acid change (Leu66Pro) in the third
exon, an exon common to both procalcitonin and pro-alpha-CGRP. In a subsequent
association study, frequencies of the identified polymorphisms in Parkinson and
schizophrenia patients were compared with frequencies in the normal population.
No statistically significant association was found in our material. The 16-bp
microdeletion polymorphism was present in a family with multiple cases of unipolar
or bipolar depressive disorder. Using this polymorphism as marker, cosegregation
with the phenotype was observed in the majority of individuals." [Abstract]
K, Watanabe A, Iwayama-Shigeno Y, Yoshikawa T.
Evidence of association
between gamma-aminobutyric acid type A receptor genes located on 5q34 and female
patients with mood disorders.
Neurosci Lett. 2003 Sep 25;349(1):9-12.
evidence suggests the involvement of gamma-aminobutyric acid (GABA) perturbation
in the etiology of mood disorders. A linkage study has detected chromosomal area
5q34, where GABA type A (GABA(A)) receptor subunit genes are mapped, as a susceptibility
region for mood disorders, making these genes compelling candidates for such diseases.
Our prior quantitative trait loci (QTL) analysis of mouse depression models identified
a QTL on mouse chromosome 11, a genomic region whose human synteny includes 5q34.
This further supports a contribution from GABA(A) receptors to a predisposition
towards mood disorder. In the present study, we examined GABA(A) receptor alpha1
(GABRA1), alpha6 (GABRA6) and gamma2 (GABRG2) subunit genes on 5q34. Polymorphisms
on GABRA1 and GABRA6 genes displayed significant associations with mood disorders
in female patients. These data offer genetic support for a role of GABA(A) receptor
genes in susceptibility to mood disorders." x[Abstract]
L, Verheyen GR, Furac I, Ivezic S, Jakovljevic M, Raeymaekers P, Van Broeckhoven
Positive association between the GABRA5 gene and unipolar recurrent
gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in
the pathogenesis of mood disorders. To test this hypothesis we carried out an
association study between a dinucleotide repeat polymorphism in the GABAA receptor
alpha 5 subunit gene and bipolar and unipolar mood disorders. Our results suggest
a possible involvement of this gene in unipolar but not in bipolar disorder."
YW, Chen TJ, Hong CJ, Chen HM, Tsai SJ.
Association Study of the
Interleukin-1beta (C-511T) Genetic Polymorphism with Major Depressive Disorder,
Associated Symptomatology, and Antidepressant Response.
2003 Apr 2; [epub ahead of print]
"Proinflammatory cytokines, including
interleukin (IL)-1beta, are suggested to have a role in the pathogenesis of major
depressive disorder (MDD) and be related to the therapeutic effects of antidepressants.
To elucidate a genetic predisposition of MDD, we studied biallelic polymorphism
in the promoter region (position -511) of the IL-1beta gene in 157 patients with
MDD and in 112 controls. We also examined the association of this polymorphism
and fluoxetine therapeutic response in 119 MDD patients who received a 4-week
fluoxetine treatment. No significant difference was found in the genetic polymorphism
between MDD patients and controls. However, MDD patients who were homozygous for
the -511T allele of the IL-1beta gene had a trend of less severity of depressive
symptoms and more favorable fluoxetine therapeutic response than -511C carriers.
Further study with a larger sample is needed to clarify the role of the IL-1beta
genetic polymorphisms in the symptoms and treatment effects in MDD." [Abstract]
TY, Pae CU, Hoon-Han, Chae JH, Bahk WM, Kim KS, Serretti A.
association between -G308A tumour necrosis factor-alpha gene polymorphism and
major depressive disorder in the Korean population.
Genet. 2003 Sep;13(3):179-81.
"SUMMARY: OBJECTIVE The present study was
aimed at examining the association between the -G308A tumour necrosis factor-alpha
gene polymorphism and major depressive disorder (MDD) in the Korean population.METHODS
One hundred and eight in-patients with MDD and 125 healthy controls participated
in this study. Genotyping was performed by polymerase chain reaction-restriction
fragment length polymorphism.RESULTS Genotype and allele distributions in patients
with MDD (P=0.024 and P=0.0125, respectively), were significantly different from
those of the controls. In particular, subjects with MDD had an increased frequency
of the TNF2 (A) allele.CONCLUSION The present study suggests that the -G308A tumour
necrosis factor-alpha gene polymorphism may have a potential role for susceptibility
to MDD in the Korean population." [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 B Neuropsychiatr Genet. 2004 May 15;127(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]
Serretti A, Zanardi R, Franchini L, Artioli P, Dotoli D, Pirovano A, Smeraldi E
Pharmacogenetics of selective serotonin reuptake inhibitor response: a 6-month follow-up.
Pharmacogenetics. 2004 Sep;14(9):607-13.
BACKGROUND: We previously reported the association between some genetic factors and short-term antidepressant outcome. In the present paper we investigated the same gene variants in a prospective 6-months naturalistic follow-up. METHODS: The sample included 185 inpatients affected by recurrent major depression consecutively admitted to the Psychiatric Inpatient Unit of San Raffaele Hospital from 1998 to 2003 and prospectively followed for 6 months after their recovery. All the patients were undertaking continuation therapy. The functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR), the tryptophan hydroxylase A218C substitution, a VNTR polymorphism located 1.2 kb upstream of the monoamine oxidase-A coding sequences, the CLOCK gene T3111C and the PER3exon15 gene T1940G substitutions were analysed, using PCR-based techniques. RESULTS: No association was found between clinical variables and relapses; subjects showing TT genotype at CLOCK gene tended to relapse within 6 months after recovery more than TC and CC subjects taken together. A non-significant tendency of SERTPR*s/s subjects to a minor frequency of relapse was also observed. CONCLUSION: Some subjects showing remission after acute treatment relapsed within 6 months, despite undertaking a maintenance treatment; the causes could be heterogeneous, but CLOCK gene variants may influence the outcome. [Abstract]
Zubenko GS, Maher BS, Hughes HB, Zubenko WN, Scott Stiffler J, Marazita ML
Genome-wide linkage survey for genetic loci that affect the risk of suicide attempts in families with recurrent, early-onset, major depression.
Am J Med Genet. 2004 Aug 15;129B(1):47-54.
We previously described the results of a genome-wide linkage survey for genetic
loci that influenced the development of unipolar mood disorders in 81 families
identified by individuals with Recurrent, Early-Onset, Major Depressive Disorder
(RE-MDD) [Zubenko et al. 2003b; Am J Med Genet (Neuropsychiatr Genet)
123B:1-18]. In the current study, we extended this linkage analysis by including
the history of a suicide attempt as a covariate to identify chromosomal regions
that harbor genes that influence the risk of this behavior in the context of
mood disorders. This approach identified six linkage peaks with maximum
multipoint DeltaLOD scores that reached genome-wide adjusted levels of
significance (2p, 5q, 6q, 8p, 11q, and Xq). Four of these (2p, 6q, 8p, and Xq)
exceeded the criterion for "highly-significant linkage" (genome-wide adjusted P < 0.001) recommended by Lander and Kruglyak [1995; Nat Genet 11:241-246]. The strongest evidence for linkage was observed in analyses employing affected relative pairs (ARPs) with the most severe and disabling Mood Disorders: Depression Spectrum Disorder and RE-MDD. The highest DeltaLOD score that emerged from this linkage analysis, 5.08, occurred for ARPs with Depression Spectrum Disorder at D8S1145 (37.0 cM, 18.2 Mbps, P < 0.0001) at cytogenetic location 8p22-p21. Significant linkage results on Xq arose from analyses of ARPs with RE-MDD at DXS1047 (143 cM, 127.8 Mbps, DeltaLOD = 3.87, P < 0.0001), a finding that may contribute to the higher rate of suicide attempts among women than men. These findings provide evidence for suicide risk loci that are independent of susceptibility loci for Mood Disorders, and suggest that the capacity for suicide risk loci to affect the development of suicidal behavior depends on the psychiatric disorder or subtype with which they interact. [Abstract]
Pae CU, Yu HS, Kim TS, Lee CU, Lee SJ, Jun TY, Lee C, Serretti A, Paik IH
Monocyte chemoattractant protein-1 (MCP1) promoter -2518 polymorphism may confer a susceptibility to major depressive disorder in the Korean population.
Psychiatry Res. 2004 Jul 15;127(3):279-81.
We conducted a case-control association study of the monocyte chemoattractant protein-1 (MCP1) gene -2518 polymorphism in 90 patients with major depressive disorder. Genotyping was performed by polymerase chain reaction methods. We found significant differences in genotype and allele frequencies. The present study suggests that this polymorphism may confer a susceptibility to major depressive disorder in the Korean population. [Abstract]