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Genetic drug target validation using Mendelian randomization

By A F Schmidt, C Finan, M Gordillo-Mara├▒├│n, F.W. Asselbergs, D F Freitag, R S Patel, B Tyl, S Chopade, R Faraway, M Zwierzyna, A D Hingorani

Posted 25 Sep 2019
bioRxiv DOI: 10.1101/781039

Mendelian randomisation analysis has emerged as an important tool to elucidate the causal relevance of a range of environmental and biological risk factors for human disease. However, inference on cause is undermined if the genetic variants used to instrument a risk factor of interest also associate with other traits that open alternative pathways to the disease (horizontal pleiotropy). We show how the "no horizontal pleiotropy assumption" in MR analysis is strengthened when proteins are the risk factors of interest. Proteins are the proximal effectors of biological processes encoded in the genome, and are becoming assayable on an -omics scale. Moreover, proteins are the targets of most medicines, so Mendelian randomization (MR) studies of drug targets are becoming a fundamental tool in drug development. To enable such studies we introduce a formal mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. Finally, we illustrate key model decisions and introduce an analytical framework for maximizing power and elucidating the robustness of drug target MR analyses.

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