Seminars in Precision Medicine
Title: Robust Mendelian randomization coupled with Alphafold2 for drug target discovery
Speaker: Zhonghua Liu, PhD
Assistant Professor of Biostatistics in the Department of Biostatistics at Mailman School of Public Health, Columbia University
Mendelian randomization (MR) uses genetic variants as instrumental variables (IVs) to estimate the causal effect of a modifiable risk factor on the outcome of interest to remove unmeasured confounding bias. However, some genetic variants might be invalid IVs due to violations of core IV assumptions, for example, in the presence of population stratification and/or widespread horizontal pleiotropy. Inclusion of invalid genetic IVs for MR analysis might lead to biased causal effect estimate and misleading scientific conclusions. To address this challenge, we propose a novel MR method that first Selects valid genetic IVs and then performs Post-selection Inference (MR-SPI) based on two-sample genome-wide summary statistics. Extensive Monte Carlo simulation studies demonstrate the superior performance of MR-SPI. We apply MR-SPI to analyze 146 exposure-outcome pairs to establish putative causal relationships. We further analyze 912 plasma proteins using the large-scale UK Biobank proteomics data in 54,219 UK Biobank participants and identify 7 proteins significantly associated with the risk of Alzheimer’s disease. We also apply AlphaFold2 to predict the three-dimensional (3D) structural alteration of these 7 proteins due to genetic variations.
This event is hosted as part of the seminar series featuring leaders in precision medicine from across the nation. Co-presented by the Center for Precision Medicine and Genomics, the Columbia Precision Medicine Initiative, and the Precision Medicine Resource of the Irving Institute for Clinical and Translational Research. This event is supported in part by a gift from Pfizer to Columbia.
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