Genetically regulated gene expression and proteins revealed discordant effects

Area of Science:

• Genomics
• Proteomics
• Systems Biology

Background:

• Gene expression (GE) and protein levels are typically strongly genetically regulated.
• The correlation between GE and protein levels is often low.
• Understanding the genetic basis of this correlation is crucial for dissecting omics layer regulation.

Purpose of the Study:

• Investigate the genetic background of the correlation between gene expression and protein levels.
• Identify similarities and differences in genetic regulation across these omics layers.
• Determine causal relationships between gene expression and protein levels.

Main Methods:

• Performed locus-wide association studies on 92 protein levels in 2,014 whole blood samples.
• Estimated genetically regulated GE across 49 GTEx v8 tissues.
• Utilized Mendelian Randomization to test for causal links of GE on protein expression.

Main Results:

• Identified 66 genetically regulated proteins, with some sex-specific effects.
• Found high correlations between genetically regulated GE and protein levels across tissues.
• Confirmed negative causal effects of GE on five protein levels (BLMH, CASP3, CXCL16, IL6R, SFTPD) in 63 gene-tissue pairs.
• Replicated a negative causal effect of IL6R GE on coronary artery disease (CAD).

Conclusions:

• Genetically regulated components of GE and protein levels correlate highly across tissues.
• Tissue-specific GE has strong negative causal effects on five protein levels.
• GE influences CAD risk, often mediated by protein levels.