Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease ...aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.
Rationale
In bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 ...(AHI1) protein, behavioural changes and innate immunity regulation. An immunomodulatory effect was suggested for lithium, a mood stabilizer used in BD treatment.
Objectives
We hypothesized that AHI1 may be an important mediator of lithium treatment response. Our study aimed to investigate whether the
AHI1
haplotypes and expression associates with lithium treatment response in BD patients. We also examined whether
AHI1
expression and lithium treatment correlate with innate inflammatory response genes.
Results
We genotyped seven
AHI1
single nucleotide polymorphisms in 97 euthymic BD patients and found that TG haplotype (rs7739635, rs9494332) was significantly associated with lithium response. We also showed significantly increased
AHI1
expression in the blood of lithium responders compared to non-responders and BD patients compared to healthy controls (HC). We analyzed the expression of genes involved in the innate immune response and inflammatory response regulation (
TLR4
,
CASP4
,
CASP5
,
NLRP3
,
IL1A
,
IL1B
,
IL6
,
IL10
,
IL18)
in 21 lithium-treated BD patients, 20 BD patients treated with other mood stabilizer and 19 HC. We found significantly altered expression between BD patients and HC, but not between BD patients treated with different mood stabilizers.
Conclusions
Our study suggests the involvement of
AHI1
in the lithium mode of action. Moreover, mood-stabilizing treatment associated with the innate immunity-related gene expression in BD patients and only the lithium-treated BD patients showed significantly elevated expression of anti-inflammatory
IL10,
suggesting lithium’s immunomodulatory potential
.
There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin ...reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene.
To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor).
The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project.
The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome.
The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.
The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and ...glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P=0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.
We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 ...X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (
NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10
−8; odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10
−4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10
−9 (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD.
NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.
Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind ...antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.
Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).
No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.
We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.
•Antidepressant efficacy, major depressive disorder and schizophrenia are complex polygenic traits.•Genetic overlap has been previously demonstrated among different psychiatric disorders.•Polygenic risk scores did not predict antidepressant efficacy between two independent samples.•Polygenic risk scores did not show overlap between antidepressant efficacy and major depressive disorder.•Polygenic risk scores did not show overlap between antidepressant efficacy and schizophrenia.
Recent studies revealed the role of the
(
) gene variability in vulnerability to posttraumatic stress disorder in women. Due to the relatively high comorbidity of posttraumatic stress disorder and ...substance use disorder, we hypothesized about possible associations between
gene and problematic alcohol use.
The sample studied consisted of 491 women aged 18-28 years (mean age =21.76 years; SD =1.83) and the Alcohol Use Disorders Identification Test was used to assess drinking problems. We successfully genotyped 17 single-nucleotide polymorphisms in the
gene.
Single locus analysis revealed a significant (after correction for multiple testing) association between intronic polymorphism rs2302475 and problematic alcohol use (
=0.00048; recessive model). This result was strengthened by the haplotype analysis (
=0.00379).
Our results suggest that the PACAP/PAC1 signaling system is implicated in the development of problematic alcohol use in women.
We have investigated the gene for dystrobrevin-binding protein 1 (DTNBP1), or dysbindin, which has been strongly suggested as a positional candidate gene for schizophrenia, in three samples of ...subjects with schizophrenia and unaffected control subjects of German (418 cases, 285 controls), Polish (294 cases, 113 controls), and Swedish (142 cases, 272 controls) descent. We analyzed five single-nucleotide polymorphisms (P1635, P1325, P1320, P1757, and P1578) and identified significant evidence of association in the Swedish sample but not in those from Germany or Poland. The results in the Swedish sample became even more significant after a separate analysis of those cases with a positive family history of schizophrenia, in whom the five-marker haplotype A-C-A-T-T showed a
P value of .00009 (3.1% in controls, 17.8% in cases; OR 6.75;
P=.00153 after Bonferroni correction). Our results suggest that genetic variation in the dysbindin gene is particularly involved in the development of schizophrenia in cases with a familial loading of the disease. This would also explain the difficulty of replicating this association in consecutively ascertained case-control samples, which usually comprise only a small proportion of subjects with a family history of disease.
Objectives: The aim of the study was to test a possible association between the Val66Met polymorphism of the brain‐derived neurotrophic factor (BDNF) gene and performance on a neurocognitive test, ...the Wisconsin Card Sorting Test (WCST), in bipolar patients.
Methods: Fifty‐four bipolar patients were studied, 18 male and 36 female, aged 18–72 (mean 46 years). The number of perseverative errors (WCST‐P), non‐perseverative errors (WCST‐NP), completed corrected categories (WCST‐CC), conceptual level responses (WCST‐%CONC) and set to the first category (WCST‐1st CAT) were measured in relation to the Val66Met genotypes of BDNF.
Results: The percentages of subjects with Val/Val, Val/Met and Met/Met genotypes were respectively 81.5, 16.7 and 1.8%. Subjects with Val/Val and Val/Met genotypes did not differ on clinical factors except for the age of onset of the illness, which was earlier in Val/Val than Val/Met genotype (27 years versus 38 years). The performance in all domains of WCST was significantly better in subjects with Val/Val BDNF genotype compared with Val/Met genotype.
Conclusions: The results suggest a role of BDNF in prefrontal cognitive function in bipolar illness. The tests of prefrontal cognition may be considered as endophenotypic markers in bipolar illness.
The authors previously reported an association between the D-amino acid oxidase activator (DAOA)/G30 locus and both schizophrenia and bipolar affective disorder. Given the presumed role of DAOA/G30 ...in the neurochemistry of psychosis and its localization in a schizophrenia and bipolar affective disorder linkage region (13q34), it was hypothesized that the bipolar affective disorder finding would be mainly due to an association with psychotic features.
The marker/haplotype associations obtained in a subset of 173 bipolar affective disorder patients with psychotic features were similar to those in the overall patient group, suggesting that stratification on the basis of psychotic features in general might be too crude a procedure. The authors therefore tested whether confining caseness to specific psychotic features would improve detection of genotype-phenotype correlations.
In a logistic regression, "persecutory delusions" were found to be the only significant explanatory variable for the DAOA/G30 risk genotype among 21 OPCRIT symptoms of psychosis. The authors therefore tested for association between DAOA/G30 and bipolar affective disorder in the 90 cases with a history of persecutory delusions. Whereas this subset showed strong association (odds ratio=1.83 for the best marker), the remaining larger sample of 165 patients with no such history did not differ from comparison subjects, suggesting that the association between DAOA/G30 and bipolar affective disorder is due to persecutory delusions. This was confirmed in an independent study of 294 bipolar affective disorder patients and 311 comparison subjects from Poland, in which an association between bipolar affective disorder and DAOA/G30 was only seen when case definition was restricted to cases with persecutory delusions.
These data suggest that bipolar affective disorder with persecutory delusions constitutes a distinct subgroup of bipolar affective disorder that overlaps with schizophrenia.
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