Colocalization and discordance between plasma and brain protein quantitative trait loci

Area of Science:

• Genetics
• Biomarker Discovery
• Systems Biology

Background:

• Protein quantitative trait loci (pQTLs) studies link genetic variants to protein levels, aiding complex trait interpretation.
• Plasma-based pQTLs are accessible but may not reflect disease-relevant tissue regulation.
• Understanding tissue specificity is key for accurate biomarker and therapeutic target identification.

Purpose of the Study:

• To assess colocalization and discordance between plasma and dorsal prefrontal cortex cis-pQTLs.
• To investigate the implications of tissue-specific regulation for downstream genetic analyses.
• To compare Mendelian randomization (MR) analyses using instruments from different tissue contexts.

Main Methods:

• Utilized data from four large-scale studies to analyze cis-pQTLs in plasma and dorsal prefrontal cortex.
• Characterized tissue-specific gene expression using Genotype-Tissue Expression (GTEx) project data.
• Performed Mendelian randomization (MR) analyses with neuroticism as the outcome.

Main Results:

• At most 80% of cis-pQTLs showed evidence of colocalization between plasma and brain tissue.
• Approximately 20% of colocalized loci exhibited opposite genetic effect directions.
• Proteins with colocalized pQTLs showed higher expression in systemic/immune tissues; others showed higher brain expression.
• MR analyses identified 13 proteins associated with neuroticism, with 6 showing opposing effects between plasma and brain.

Conclusions:

• Circulating pQTLs are informative for systemic and immune proteins but may miss tissue-specific regulation.
• Incorporating tissue-specific data refines interpretation of protein-trait associations.
• Considering multiple tissue contexts improves prioritization of candidate biomarkers and therapeutic targets.