Genetic drug target validation using Mendelian randomisation
By A. Schmidt, C. Finan, M. Gordillo-Marañón, F. Asselbergs, D. Freitag, R. Patel, B. Tyl, S. Chopade, Rupert Faraway, M. Zwierzyna and 1 more. Nature Communications, 2020
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Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, causal inference is undermined if genetic variants used to instrument a risk factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how the ‘no horizontal pleiotropy assumption’ is strengthened when proteins are the risk factors of interest. Proteins are typically the proximal effectors of biological processes encoded in the genome. Moreover, proteins are the targets of most medicines, so MR studies of drug targets are becoming a fundamental tool in drug development. To enable such studies, we introduce a mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. We illustrate key model decisions and introduce an analytical framework for maximising power and evaluating the robustness of analyses. Mendelian randomisation (MR) analysis of drug targets has potential to aid drug development. Here, the authors introduce a mathematical framework to elucidate this specific application of MR.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/9770f8c303cdd730a00685a4b9d9dfd9fbaf8d24
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Citations in the corpus
- Plasma proteomic associations with genetics and health in the UK Biobank (2023, background): “11 and Supplementary Table 28); (3) common genetic variation has a subtle, but significant, role in inflammasome-mediated innate immune responses (Supplementary Table 29); and (4) large-scale proteogenomics studies can increase the power and availability of genetic instruments for Mendelian randomiz”
- Mendelian randomization for cardiovascular diseases: principles and applications (2023, unknown): “93 In brief, most drugs act by targeting proteins, which are coded for by genes.”