Proteome-Wide Mendelian Randomization Identifies Candidate Causal Proteins for Cardiovascular Diseases

Area of Science:

• Genetics
• Proteomics
• Cardiovascular Disease Research

Background:

• Integrating human genomics and omics data across ancestries offers a systematic approach for identifying drug targets.
• Cardiovascular diseases (CVDs) remain a leading cause of mortality, necessitating novel therapeutic strategies.

Purpose of the Study:

• To unravel causal associations between circulating proteins and 19 CVDs using Mendelian randomization (MR).
• To identify novel protein targets for CVD drug discovery through human genetics-based evidence.

Main Methods:

• Utilized forward and reverse Mendelian randomization (MR) analyses.
• Investigated associations between 2,940 circulating proteins and 19 CVDs.
• Replicated findings using FinnGen Olink data and integrated single-cell data.

Main Results:

• Identified 218 proteins impacting risk for one or more CVDs via forward MR.
• Replicated 102 proteins associated with CVD risk in independent datasets.
• Highlighted BTN3A2 as a novel candidate for ischemic stroke and prioritized PAM and LPL for other CVDs.

Conclusions:

• The study provides robust human genetics-based evidence for novel candidate genes in CVD.
• Findings support a foundational step towards causal human biology-based drug discovery for CVD.
• Identified distinct proteomic causes and consequences of CVD through forward and reverse MR analyses.