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Updated: Feb 17, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Systematic Druggable Genome-Wide Mendelian Randomization Identifies Genetically Supported Therapeutic Targets for

Boteng Yan1,2, Peijiang Pan3, Wenfu Tao4

  • 1Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.

Current Medicinal Chemistry
|February 15, 2026
PubMed
Abstract

Insights

This study used Mendelian randomization to identify 66 genetically supported therapeutic targets for coronary artery disease (CAD). Key genes like ERP29, MCL1, TNXB, MAPK3, and TNF show promise for novel CAD treatments.

Area of Science:

  • Genetics
  • Pharmacology
  • Cardiovascular Medicine

Background:

  • Coronary artery disease (CAD) is a major global cause of death with limited treatment options.
  • Identifying genetically validated therapeutic targets is crucial for developing effective CAD therapies.

Purpose of the Study:

  • To identify and prioritize genetically supported therapeutic targets for CAD using Mendelian randomization (MR).
  • To investigate potential mechanisms and on-target effects of these targets.

Main Methods:

  • A two-sample MR framework analyzed causal effects of blood cis-expression quantitative trait loci (cis-eQTLs) on CAD.
  • Steiger filtering, Bayesian colocalization, and sensitivity analyses consolidated MR findings.
  • Mediation and phenome-wide MR analyses explored mechanisms and gene effects.

Main Results:

  • Identified 66 causal druggable genes associated with CAD in European populations.
  • ERP29, MCL1, TNXB, DAGLB, FES, and TRPM4 colocalized with CAD and were replicated in an East Asian cohort.
  • MAPK3 and TNF were highlighted as prioritized targets, with mediation analysis revealing links to BMI, triglycerides, blood pressure, and atrial fibrillation.

Conclusions:

  • The study validated known CAD drug targets and discovered novel genes (ERP29, MCL1, TNXB, DAGLB, FES, TRPM4) implicated in blood pressure and lipid metabolism.
  • MAPK3 and TNF show promise as druggable targets, potentially offering benefits for related cardiometabolic disorders.
  • Further research is needed to explore the clinical feasibility and generalizability of these identified targets.
Keywords:
Coronary artery diseasedruggable Mendelian randomizationexpression quantitative trait loci.therapeutic targets

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