A Robust Cis-Mendelian Randomization Method with Application to Drug Target Discovery

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jul 18

PMID 39025905

Authors

Zhaotong Lin

Wei Pan

Affiliations

Soon will be listed here.

Abstract

Mendelian randomization (MR) uses genetic variants as instrumental variables (IVs) to investigate causal relationships between traits. Unlike conventional MR, cis-MR focuses on a single genomic region using only cis-SNPs. For example, using cis-pQTLs for a protein as exposure for a disease opens a cost-effective path for drug target discovery. However, few methods effectively handle pleiotropy and linkage disequilibrium (LD) of cis-SNPs. Here, we propose cisMR-cML, a method based on constrained maximum likelihood, robust to IV assumption violations with strong theoretical support. We further clarify the severe but largely neglected consequences of the current practice of modeling marginal, instead of conditional genetic effects, and only using exposure-associated SNPs in cis-MR analysis. Numerical studies demonstrated our method's superiority over other existing methods. In a drug-target analysis for coronary artery disease (CAD), including a proteome-wide application, we identified three potential drug targets, PCSK9, COLEC11 and FGFR1 for CAD.

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