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

Abstract

Protein quantitative trait loci (pQTLs) are an invaluable source of information for drug target development because they provide genetic evidence to support protein function, suggest relationships between cis- and trans-associated proteins, and link proteins to disease endpoints. Using Olink proteomics data for 1,463 proteins measured in over 54,000 samples of the UK Biobank, we identified 4,248 associations with 2,821 ratios between protein levels (rQTLs). rQTLs were 7.6-fold enriched in known protein-protein interactions, suggesting that their ratios reflect biological links between the implicated proteins. Conducting a GWAS on ratios increased the number of discovered genetic signals by 24.7%. The approach can identify novel loci of clinical relevance, support causal gene identification, and reveal complex networks of interacting proteins. Taken together, our study adds significant value to the genetic insights that can be derived from the UKB proteomics data and motivates the wider use of ratios in large-scale GWAS.

Graphical abstract

Figure 1

Percentage of Bonferroni significant protein ratio pair associations (p-gain >10 × 179,923) as a function of the partial correlation |pcor| between the protein pair A moving average with a window size of 10,000 data points was used.

Figure 2

Two-dimensional Manhattan plots (A) The position of the rQTL plotted against the position of the genes coding for the two proteins in the ratio, the stronger of the two single protein associations is in blue, the weaker in red. (B) The positions of the genes coding for the two proteins in an rQTL ratio plotted against each other; darker colors indicate multiple rQTLs with the same ratio.

Figure 3

Regional association plot for the association of the HAGH/PKLR ratio at a major IBD locus on Chr3 Plot created using LocusZoom.

Figure 4

Possible scenarios that can lead to a significant p-gain in a ratio association P1 and P2 are the proteins in the ratio that associates with the genetic variant SNP, X is the causal cis-encoded protein in the case of a trans-rQTLs, and W denotes some unidentified shared nongenetic variance.

Figure 5

Example of a ratio that leads to the discovery of novel signals (A–C) Manhattan plots for the GWAS with (A) ITGB1BP2, (B) MITD1, and (C) the ratio ITGB1BP2/MITD1. Associations with p values exceeding 10⁻²⁰ are indicated by red triangles. Vertical lines indicate 24 Bonferroni-significant (p < 5 × 10⁻⁸/2821) rQTLs for the ratio. Manhattan plots for all 2,821 ratio GWAS are available as online (Figure S1 and Data S1, https://doi.org/10.6084/m9.figshare.23695398).