Proteome-Wide Association Studies for Blood Lipids and Comparison with Transcriptome-Wide Association Studies

Area of Science:

• Genetics
• Cardiovascular Disease
• Metabolomics

Background:

• Blood lipid traits (total cholesterol, triglycerides, HDL, LDL) are heritable risk factors for heart disease, a leading global cause of mortality.
• Genome-wide association studies (GWAS) have identified numerous genetic variants linked to lipids, but causal mechanisms remain largely unknown.
• Understanding lipid metabolism is crucial for developing effective heart disease prevention and treatment strategies.

Approach:

• Conducted proteome-wide association studies (PWAS) by training protein prediction models on Multi-Ethnic Study of Atherosclerosis (MESA) samples and applying them to Global Lipids Genetics Consortium (GLGC) data.
• Investigated associations between 749 plasma protein levels and four key lipid traits (TC, TG, HDL, LDL).
• Performed transcriptome-wide association studies (TWAS) using gene expression prediction models from MESA (peripheral blood mononuclear cells) and GTEx (49 tissues) to complement PWAS findings.

Key Points:

• Identified 42 proteins significantly associated with at least one blood lipid trait through PWAS.
• Observed a high-level consistency between proteome-lipid and transcriptome-lipid associations across multiple tissues.
• Found that 40 out of 49 tissues showed a positive correlation between PWAS and TWAS signed p-values, despite potential differences in individual gene associations.

Conclusions:

• Plasma protein levels are significantly associated with blood lipid traits, offering new insights into lipid metabolism.
• PWAS and TWAS provide complementary information, and their combined findings suggest a robust link between the proteome, transcriptome, and lipid regulation.
• These findings advance our understanding of the biological pathways underlying lipid metabolism and their connection to cardiovascular health.