Network-based integrative analysis of lithium response in bipolar disorder using transcriptomic and GWAS data
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ABSTRACT:
PROVIDER: PRJNA844997 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR19529160.fastq.gz | Fastqsanger.gz | |||
| SRR19529161.fastq.gz | Fastqsanger.gz | |||
| SRR19529162.fastq.gz | Fastqsanger.gz | |||
| SRR19529163.fastq.gz | Fastqsanger.gz | |||
| SRR19529164.fastq.gz | Fastqsanger.gz |
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Project description:Lithium is the gold standard treatment for bipolar disorder. The goal of this study was to identify gene expression networks associated with lithium response. RNAseq data was obtained from IPSC derived neurons from lithium responders and non-responders. Focal adhesion was the network most associated with response.
2022-06-09 | GSE205422 | GEO
Project description:Bipolar disorder is a severe and heritable psychiatric disorder and affects up to 1% of the population worldwide. Lithium is recommended as first-line treatment for the maintenance treatment of bipolar-affective disorder in current guidelines, its molecular modes of action are however poorly understood. Cell models derived from bipolar patients could prove useful to gain more insight in the molecular mechanisms of bipolar disorder and the common pharmacological treatments. As primary neuronal cell lines cannot be easily derived from patients, peripheral cell models should be evaluated in their usefulness to study pathomechanisms and the mode of action of medication as well as in regard to develop biomarkers for diagnosis and treatment response.
2018-12-01 | GSE66196 | GEO
Project description:BACKGROUND: Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use. METHODS: We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk. RESULTS: While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD. CONCLUSIONS: These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.
2019-10-24 | GSE124326 | GEO
Project description:Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect
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Project description:Metabolic alterations have been observed in the brains of patients with bipolar disorder (BD), a neuropsychiatric disorder characterized by biphasic mood episodes of mania and depression. However, the specific contributions of glial cells to these metabolic changes in BD patients remain largely unknown and have not been extensively studied. Here, we investigate the metabolic characteristics of induced astrocytes (iAstrocytes) derived from induced pluripotent stem cells of BD patients and their responses to lithium treatment. The gene expression profiles of iAstrocytes from BD patients (BD iAstrocytes) indicate dysregulation of metabolic processes in BD iAstrocytes. Compared to iAstrocytes from control subjects, BD iAstrocytes showed decreased mitochondrial respiration, increased glycolysis, and elevated lactate secretion. These changes in metabolic pathways suggest impaired mitochondrial function. Additionally, we observed reduced protein expression within the oxidative phosphorylation complex and decreased reactive oxygen species production, further supporting the impaired mitochondrial function in BD iAstrocytes. Intriguingly, BD iAstrocytes showed an accumulation of lipid droplets (LDs) in both volume and number, possibly reflecting metabolic stress-induced LD accumulation. Lithium, a commonly prescribed treatment for BD, selectively attenuated LD accumulation exclusively in BD iAstrocytes from lithium responders, while it failed to restore mitochondrial dysfunction and increased lactate secretion. Our findings provide novel insights into understanding the metabolic dysfunction in the brains of BD patients and shed light on molecular mechanisms of lithium action, particularly regarding astrocytes. The LDs in BD iAstrocytes from lithium non-responders may serve as a useful readout for drug screening to identify suitable medications for these patients.
2025-08-20 | GSE241671 | GEO
Project description:Bipolar disorder (BD) (1% of the general population) is a major affective disorder characterized by recurrent manic and depressive episodes and associated with considerable burden and costs. Lithium (Li) is the first line treatment for relapse prevention in bipolar disorders with many patients who remain asymptomatic for several years (even decades). In addition, it is the only psychoactive drug that has demonstrated efficacy in suicide prevention. However a large proportion of patients is experiencing very high relapse rates (overall between 70 and 80% relapse, 2 years after a major episode). Li mechanism of action is rather complex and still not fully understood despite extensive studies. In order to explore potential lithium effects on global gene and miRNAs expression, we initiated a study in cell-lines from excellent responders (ER) and non-responders (NR) bipolar patients Briefly, long-term treatment response to lithium was evaluated using a validated scale “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” , also known as the Alda scale. In our sample we analyzed dichotomous phenotypes for lithium response: patients with total score (TS) higher or equal to 7, characterized as ER; and patients with TS lower than 2, characterized as NR according to the literature.
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Project description:Bipolar disorder (BD) (1% of the general population) is a major affective disorder characterized by recurrent manic and depressive episodes and associated with considerable burden and costs. Lithium (Li) is the first line treatment for relapse prevention in bipolar disorders with many patients who remain asymptomatic for several years (even decades). In addition, it is the only psychoactive drug that has demonstrated efficacy in suicide prevention. However a large proportion of patients is experiencing very high relapse rates (overall between 70 and 80% relapse, 2 years after a major episode). Li mechanism of action is rather complex and still not fully understood despite extensive studies. In order to explore potential lithium effects on global gene and miRNAs expression, we initiated a study in cell-lines from excellent responders (ER) and non-responders (NR) bipolar patients Briefly, long-term treatment response to lithium was evaluated using a validated scale “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” , also known as the Alda scale. In our sample we analyzed dichotomous phenotypes for lithium response: patients with total score (TS) higher or equal to 7, characterized as ER; and patients with TS lower than 2, characterized as NR according to the literature.
2017-07-04 | GSE93113 | GEO
Project description:Lithium treatment is commonly used to treat bipolar disorder. However, this treatment disrupts kidney fuctionality. We used microdissected cortical collecting ducts to study proteomics and ultimately discover what changes occur in protein expression after 72-hr lithium treatment.
2019-07-01 | PXD010118 | Pride
Project description:Human neuronal-like cells (NT2-N) were treated with either lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), valproate (0.5 mM) or vehicle control for 24 hours. Genome wide mRNA expression was quantified by RNA-sequencing. Results offer insights on the mechanism(s) of action of bipolar disorder drugs at the transcriptional level.
2022-04-08 | GSE197966 | GEO
Project description:Bipolar Disorder (BD) is a chronic psychiatric illness affecting ~3% of the global population. It is one of the top 10 causes of disability and mortality worldwide, largely due to high suicide, cardiovascular, and metabolic comorbidity. Typically, BD has life-long presentation characterized by alternations of extreme mania and depression, associated with psychosis and self-harm. Given the complex heritability and symptoms of BD, long term clinical management of some patients remains unsatisfactory. Thus, there is a major unmet need for new clinical treatment strategies and drug options to help these patients. Lithium (Li) remains the gold standard mood stabilizer and first-line treatment for manic/depressive episodes, reducing suicide and overall mortality rates. Two major questions stand out i) how Li is effective, and ii) why for only a subset of patients? To address this, we studied the biology and lithium effects in iPSC-derived neurons from people with a known clinical and genetic profile, comparing healthy individuals, BD Li-responders, and BD Li-non responders. We combined cell imaging, electrophysiology, biochemistry, , phosphoproteomic and whole transcriptome sequencing approaches to provide mechanistic insights and guide the search for BD biomarkers and Li responsiveness.
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