Genetic associations with ratios between protein levels detect new pQTLs and reveal protein-protein interactions

• Novel Method: Introduces Ratio-QTLs (rQTLs), a proteogenomic method that analyzes the genetic determinants of ratios between pairs of plasma protein levels rather than individual protein levels.
• Key Finding: The rQTL approach provided an enormous increase in statistical power, strengthening associations at known pQTL loci by several hundred orders of magnitude (p-gain) and enabling the discovery of new cis-pQTLs.
• Biological Relevance: rQTLs were 7.6-fold enriched in established Protein-Protein Interactions (PPIs), confirming the method’s unique ability to uncover genetic variants that regulate the functional interaction or shared biological regulation between two proteins.

PubMed: 38412862 DOI: 10.1016/j.xgen.2024.100506 Overview generated by: Gemini 2.5 Flash, 28/11/2025

Key Findings: The Power of Ratio-QTLs (rQTLs)

This study introduces a novel concept in proteomic genetics: the systematic analysis of ratios between protein levels to identify ratio quantitative trait loci (rQTLs). The central finding is that using protein ratios dramatically enhances the statistical power to detect genetic variants influencing protein regulation, particularly those linked to functional biological mechanisms like Protein-Protein Interactions (PPIs).

Enhanced Detection and Biological Relevance

• Increased Association Strength: Analyzing ratios between protein pairs, rather than individual protein levels, strengthened associations at known pQTL loci by several hundred orders of magnitude (p-gain).
• New Loci: The use of ratios increased the number of proteogenomic loci by 25% and helped detect 39 previously unidentified cis-pQTLs.
• PPI Enrichment: The identified rQTLs were 7.6-fold enriched in established protein-protein interactions (PPIs) from the BioGRID database. This high enrichment indicates that the ratio method is particularly effective at capturing genetic effects that modulate the functional interaction or shared regulation of two proteins.

Methods and Study Design

Data and Cohort

• Cohort: A large-scale analysis using proteomic and genetic data from 52,705 samples in the UK Biobank.
• Proteome: Measured levels for 1,473 plasma proteins using the Olink Proximity Extension Assay (PEA).
• Statistical Approach: The study analyzed approximately 1.1 million protein ratios, testing each ratio against genetic variants (SNPs) to find rQTLs.

Theoretical Interpretation of rQTLs

An rQTL signal between two proteins (\(P_1/P_2\)) can arise from three primary scenarios:

1. Shared Confounder: A genetic variant influences a common confounding factor (e.g., cell type composition, inflammation) that affects both proteins similarly.
2. Shared Pathway: A variant affects a shared regulatory pathway (e.g., transcription factor) controlling both proteins.
3. Protein-Protein Interaction (PPI): A variant directly or indirectly alters the functional or physical interaction between \(P_1\) and \(P_2\). The strong enrichment of rQTLs in known PPIs suggests this method excels at identifying the latter two, especially PPIs.

Results: Case Studies and Functional Insights

High-Impact rQTLs

The study highlighted several high-impact rQTLs with strong biological relevance:

• Complement Components: The strongest associations involved proteins in the complement system, an essential part of the innate immune response. The rQTL analysis revealed variants impacting the balance of activation and regulation components, such as C3/C4 and C5/C9.
• Duffy Blood Group (ACKR1): A classic example was the rQTL signal for the Duffy blood type variant (rs12075 in ACKR1). While this variant is known to affect multiple cytokine levels individually, the ratio analysis significantly amplified the association, indicating a shared, highly coordinated regulatory effect on a panel of cytokines.
• NFATC1 Pathway: The analysis revealed rQTLs regulating the ratio of NFATC1 with several other proteins, pointing to complex regulatory mechanisms related to the NFATC1-mediated signaling pathway.

Conclusions and Recommendations

The concept of rQTLs provides a powerful and generalizable theoretical framework for detecting subtle genetic effects that modulate the relative abundance of protein pairs. By focusing on ratios, researchers can effectively filter out much of the biological noise and shared technical variation that obscures signals in single-protein pQTL analyses. The high enrichment for known PPIs validates rQTLs as a superior method for identifying functional protein relationships and should be a standard approach in future proteogenomic studies for drug target discovery. The authors recommend further theoretical development and generalization of the ratio concept.