A0990
Title: Robust Mendelian randomization coupled with Alphafold2 for drug target discovery
Authors: Zhonghua Liu - Columbia University (United States) [presenting]
Abstract: Mendelian randomization (MR) uses genetic variants as instrumental variables (IVs) to infer the causal effect of a modifiable exposure on the outcome of interest by removing unmeasured confounding bias. However, some genetic variants might be invalid IVs due to violations of core IV assumptions. MR analysis with invalid IVs might lead to biased causal effect estimates and misleading scientific conclusions. To address this challenge, a novel MR method is proposed to select valid genetic IVs and then perform post-selection inference (MR-SPI) based on two-sample genome-wide summary statistics. Nine hundred twelve plasma proteins were analyzed using the large-scale UK Biobank proteomics data in 54,306 participants, and seven proteins were identified as significantly associated with the risk of Alzheimer's disease. AlphaFold2 is employed to predict the 3D structural alterations of these seven proteins due to missense genetic variations, providing new insights into their biological functions in disease etiology.
