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- Hughes, T., et al.
(författare)
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Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder
- 2018
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis pvalues: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3's association with bipolar disorder.
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| 3. |
- Abe, C., et al.
(författare)
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Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex
- 2021
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Ingår i: Journal of Psychiatry & Neuroscience. - : CMA Joule Inc.. - 1180-4882 .- 1488-2434. ; 46:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bipolar disorder is highly heritable and polygenic. The polygenic risk for bipolar disorder overlaps with that of schizophrenia, and polygenic scores are normally distributed in the population. Bipolar disorder has been associated with structural brain abnormalities, but it is unknown how these are linked to genetic risk factors for psychotic disorders. Methods: We tested whether polygenic risk scores for bipolar disorder and schizophrenia predict structural brain alterations in 98 patients with bipolar disorder and 81 healthy controls. We derived brain cortical thickness, surface area and volume from structural MRI scans. In post-hoc analyses, we correlated polygenic risk with functional hub strength, derived from resting-state functional MRI and brain connectomics. Results: Higher polygenic risk scores for both bipolar disorder and schizophrenia were associated with a thinner ventromedial prefrontal cortex (vmPFC). We found these associations in the combined group, and separately in patients and drug-naive controls. Polygenic risk for bipolar disorder was correlated with the functional hub strength of the vmPFC within the default mode network. Limitations: Polygenic risk is a cumulative measure of genomic burden. Detailed genetic mechanisms underlying brain alterations and their cognitive consequences still need to be determined. Conclusion: Our multimodal neuroimaging study linked genomic burden and brain endophenotype by demonstrating an association between polygenic risk scores for bipolar disorder and schizophrenia and the structure and function of the vmPFC. Our findings suggest that genetic factors might confer risk for psychotic disorders by influencing the integrity of the vmPFC, a brain region involved in self-referential processes and emotional regulation. Our study may also provide an imaging-genetics vulnerability marker that can be used to help identify individuals at risk for developing bipolar disorder.
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| 5. |
- Song, J., et al.
(författare)
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Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:9, s. 1290-1297
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Tidskriftsartikel (refereegranskat)abstract
- Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P = 2.74 x 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
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| 9. |
- Joas, Erik, 1983, et al.
(författare)
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Pharmacological treatment and risk of psychiatric hospital admission in bipolar disorder
- 2017
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Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 210:3, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- Background Clinical trials have examined the efficacy of drugs to prevent relapse in patients with bipolar disorder, however, their design often limits generalisation to routine clinical practice. To estimate the effectiveness of drugs used for maintenance treatment in bipolar disorder. We used national registers to identify 35 022 individuals diagnosed with bipolar disorder and information on lithium, valproate, carbamazepine, lamotrigine, quetiapine and olanzapine treatment from 2006 to 2009. The main outcome was psychiatric hospital admissions. We used stratified cox regression to compare periods on and off medication within the same individual. Medication with lithium, valproate, lamotrigine, olanzapine and quetiapine was associated with reduced rates of admission to hospital. Lithium was more effective than quetiapine and olanzapine. The effects of specific drugs depended on the polarity of the mood episode. Our findings complement results from randomised controlled trails, but suggest that lithium is more effective than both quetiapine and olanzapine in routine clinical practice.
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