Identification of novel drug targets for multiple sclerosis by integrating plasma genetics and proteomes

Liu, Yi; Wang, Qian; Zhao, Yuhui; Liu, Liu; Hu, Jingxi; Qiao, Yao; Chen, Jinyi; Qin, Chao

doi:10.1016/j.exger.2024.112505

Cited by 2 publications

References 21 publications

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Multi-omics integration prioritizes potential drug targets for multiple sclerosis

Jiang,

Liu,

Stridh

et al. 2024

Preprint

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Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease with limited treatment options. Thus, drug discovery and repurposing are essential to enhance treatment efficacy and safety. Methods: We obtained summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma proteins and 1,443 brain proteins, a genome-wide association study (GWAS) of MS susceptibility with 14,802 cases and 26,703 controls, and expression quantitative trait loci (eQTL) for 8,000 genes in peripheral blood and 16,704 genes in brain tissue. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization (SMR) to determine causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing SMR, HEIDI, and colocalization analyses were considered potential drug targets. We further conducted pathway annotations, protein-protein interaction (PPI) network analysis, and examined mRNA levels of these targets. Results: We identified hundreds of MS-associated proteins in plasma and brain, confirming the causal roles of 18 proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also discovered intricate PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. Combining expression data, we identified two targets adhering to the central dogma of molecular biology. Discussion: We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for drug discovery and repurposing in MS.

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Multi-omics integration prioritizes potential drug targets for multiple sclerosis

Jiang,

Liu,

Stridh

et al. 2024

Preprint

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Common pitfalls in drug target Mendelian randomization and how to avoid them

Gill,

Dib,

Cronjé

et al. 2024

BMC Med

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Background Drug target Mendelian randomization describes the use of genetic variants as instrumental variables for studying the effects of pharmacological agents. The paradigm can be used to inform on all aspects of drug development and has become increasingly popular over the last decade, particularly given the time- and cost-efficiency with which it can be performed even before commencing clinical studies. Main body In this review, we describe the recent emergence of drug target Mendelian randomization, its common pitfalls, how best to address them, as well as potential future directions. Throughout, we offer advice based on our experiences on how to approach these types of studies, which we hope will be useful for both practitioners and those translating the findings from such work. Conclusions Drug target Mendelian randomization is nuanced and requires a combination of biological, statistical, genetic, epidemiological, clinical, and pharmaceutical expertise to be utilized to its full potential. Unfortunately, these skillsets are relatively infrequently combined in any given study.

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Identification of novel drug targets for multiple sclerosis by integrating plasma genetics and proteomes

Cited by 2 publications

References 21 publications

Multi-omics integration prioritizes potential drug targets for multiple sclerosis

Multi-omics integration prioritizes potential drug targets for multiple sclerosis

Common pitfalls in drug target Mendelian randomization and how to avoid them

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