Druggable genome-wide Mendelian randomization for identifying the role of integrated stress response in therapeutic targets of bipolar disorder

Metformin may affect patients with multi-comorbid bipolar disorder through the integrated stress response, but their relationship remains unclear This study aimed to explore the relationship between metformin use and early (30-day) readmission in bipolar disorder patients. Data were extracted from the Medical Information Mart for Intensive Care IV database. Adult patients with a documented diagnosis of bipolar disorder were screened. Multivariable logistic regression and propensity score matching were used to investigate any association. Data on 1688 patients were included. The crude early (30-day) readmission was significantly higher in patients with metformin use (17/114 vs. 132/1574 p = 0.033). In the extended multivariable logistic models, the hazard ratio (HR) of metformin use was consistently significant in all models (HR range 1.87–2.99, p < 0.05 for all). After propensity score matching, the early (30-day) readmission remained significantly higher in the metformin use group (|t|>1.64). Although residual confounding cannot be excluded, metformin use is associated with higher readmission.

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Genetic Analysis of Psychosis Biotypes: Shared Ancestry-Adjusted Polygenic Risk and Unique Genomic Associations

Xia,

Alliey-Rodriguez,

Tamminga

et al. 2024

Preprint

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The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder and bipolar disorder with psychosis. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes and isoforms showed significant genomic associations with specific Biotypes in Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in adult brain and fetal brain. TWAS inflation was addressed by inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes TMEM140, ARTN, C1orf115, CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.

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Druggable genome-wide Mendelian randomization for identifying the role of integrated stress response in therapeutic targets of bipolar disorder

Cited by 3 publications

References 90 publications

Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Metformin Use and Thirty-Day Readmission Among Patients with Bipolar Disorders: A Propensity Score-matching Analysis

Genetic Analysis of Psychosis Biotypes: Shared Ancestry-Adjusted Polygenic Risk and Unique Genomic Associations

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