Proteome-wide association studies for blood lipids and comparison with transcriptome-wide association studies

Area of Science:

• Genetics
• Cardiovascular Disease Research
• Proteomics

Background:

• Blood lipid traits are heritable risk factors for heart disease.
• Genome-wide association studies (GWASs) have identified many human lipid-associated variants, but causal mechanisms remain largely unknown.
• Understanding lipid metabolism is crucial for cardiovascular health.

Purpose of the Study:

• To investigate associations between plasma protein levels and major blood lipid traits.
• To explore the relationship between proteome-wide and transcriptome-wide associations with lipids.
• To identify potential biological pathways underlying lipid metabolism.

Main Methods:

• Proteome-wide association studies (PWASs) were conducted using protein prediction models trained on Multi-Ethnic Study of Atherosclerosis (MESA) samples and Global Lipids Genetics Consortium (GLGC) data.
• Transcriptome-wide association studies (TWASs) were performed using gene expression prediction models from MESA and the Genotype-Tissue Expression (GTEx) project.
• Associations between PWAS and TWAS results for lipids were analyzed across multiple tissues.

Main Results:

• 42 out of 749 tested proteins showed significant associations with at least one lipid trait (total cholesterol, triglycerides, HDL, LDL).
• A high-level consistency was observed between proteome-lipid and transcriptome-lipid associations, with 40 out of 49 tissues showing positive correlation.
• PWAS and TWAS identified distinct and overlapping associations, providing a multi-omic perspective on lipid regulation.

Conclusions:

• Plasma protein levels are significantly associated with key blood lipid traits.
• Proteomic and transcriptomic data offer complementary insights into the genetic architecture of lipid metabolism.
• These findings advance our understanding of the biological underpinnings of lipid disorders and heart disease risk.