{"title":"Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes.","authors":"Tingting Jia, Tiancheng Liu, Shiyi Hu, Yongjun Li, Peixi Chen, Fengqin Qin, Yongji He, Feng Han, Chengcheng Zhang","doi":"10.1017/S0033291724001077","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>There is a clear demand for innovative therapeutics for bipolar disorder (BD).</p><p><strong>Methods: </strong>We integrated the largest BD genome-wide association study (GWAS) dataset (<i>N</i><sub>Case</sub> = 41 917, <i>N</i><sub>Control</sub> = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (<i>N</i><sub>Case</sub> = 1064, <i>N</i><sub>Control</sub> = 365 476) and the FinnGen study (<i>N</i><sub>Case</sub> = 7006, <i>N</i><sub>Control</sub> = 329 192) for robust biological validation.</p><p><strong>Results: </strong>Through MR analysis, we found that in the brain, downregulation of <i>DNM3</i>, <i>MCTP1</i>, <i>ABCB8</i> and elevation of <i>DFNA5</i> and <i>PDF</i> were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of <i>FRZB</i>, <i>AGRP</i>, and <i>IL36A</i> and decreased <i>CTSF</i> and <i>LRP8</i>. Plasma analysis revealed that decreased <i>LMAN2L</i>, <i>CX3CL1</i>, <i>PI3</i>, <i>NCAM1</i>, and <i>TIMP4</i> correlated with increased BD risk, but <i>ITIH1</i> did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for <i>LRP8</i>. External validation further underscored the concordance between the primary and validation cohorts, confirming <i>MCTP1</i>, <i>DNM3</i>, <i>PDF</i>, <i>CTSF</i>, <i>AGRP</i>, <i>FRZB</i>, <i>LMAN2L</i>, <i>NCAM1</i>, and <i>TIMP4</i> are intriguing targets for BD.</p><p><strong>Conclusions: </strong>Our study identified druggable proteins for BD, including <i>MCTP1</i>, <i>DNM3</i>, and <i>PDF</i> in the brain; <i>CTSF</i>, <i>AGRP</i>, and <i>FRZB</i> in cerebrospinal fluid; and <i>LMAN2L</i>, <i>NCAM1</i>, and <i>TIMP4</i> in plasma, delineating promising avenues to development of novel therapies.</p>","PeriodicalId":20891,"journal":{"name":"Psychological Medicine","volume":null,"pages":null},"PeriodicalIF":5.9000,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychological Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1017/S0033291724001077","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: There is a clear demand for innovative therapeutics for bipolar disorder (BD).
Methods: We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation.
Results: Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD.
Conclusions: Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.
期刊介绍:
Now in its fifth decade of publication, Psychological Medicine is a leading international journal in the fields of psychiatry, related aspects of psychology and basic sciences. From 2014, there are 16 issues a year, each featuring original articles reporting key research being undertaken worldwide, together with shorter editorials by distinguished scholars and an important book review section. The journal''s success is clearly demonstrated by a consistently high impact factor.