Proteogenomic links to human metabolic diseases

Area of Science:

• Genomics
• Proteomics
• Metabolomics
• Systems Biology

Background:

• The plasma proteome acts as a crucial link between an individual's genome and their observable traits (phenome).
• Understanding these links can uncover novel disease mechanisms and identify therapeutic targets.

Purpose of the Study:

• To conduct a cis-focused proteogenomic analysis of plasma proteins.
• To identify novel protein quantitative trait loci (pQTLs) and their association with health outcomes.
• To explore the genetic regulation of plasma proteins and their role in metabolic diseases.

Main Methods:

• Analyzed 2,923 plasma proteins in 1,180 individuals using antibody-based assays.
• Performed a cis-focused proteogenomic analysis to identify protein quantitative trait loci (pQTLs).
• Investigated shared genetic regulation between pQTLs and 575 health outcomes.

Main Results:

• Identified 256 novel protein quantitative trait loci (pQTLs).
• Demonstrated shared genetic regulation for 224 cis-pQTLs with 575 health outcomes, including links to metabolic diseases.
• Improved causal gene assignment at 40% of overlapping risk loci.
• Observed convergence between cis-pQTLs and rare loss-of-function gene burden for 12 proteins, such as TIMD4 in lipoprotein metabolism.

Conclusions:

• Integrating proteomics and genomics, even at a moderate scale, is valuable for discovering disease mediators.
• Findings highlight potential therapeutic targets for metabolic diseases, such as gastrin-releasing peptide for type 2 diabetes.
• This approach advances the understanding of genotype-phenotype relationships and disease pathogenesis.