When the proteome meets the metabolome observational and Mendelian randomization analyses

The basis for protein synthesis is the genetic code. Many of these proteins will affect intermediary metabolites by acting as enzymes, hormones, or by other actions. The aim of the present study was to assess the relationships of a large number of proteins with endogenous metabolites.

Plasma protein levels were measured by the proximity extension assay (PEA) and metabolites by mass spectrometry. Cross-sectional relationships of 242 proteins and 790 metabolites were evaluated in the EpiHealth and POEM studies using a discovery/validation approach. Genetic instruments identified in UK Biobank for protein levels (n = 1621) and genetics for metabolite levels (n = 777) in SCAPIS and EpiHealth were employed for Mendelian randomization (MR) analysis regarding putative causal associations.

In the observational analyses, 20% of the evaluated pairwise protein-metabolite associations were found significant in both the discovery and validation samples. We could however only find support for causal effects in the MR analysis for <0.1% of the pairwise associations, representing 326 unique proteins. The R² for the relationship between the MR and observational estimates was only 0.05. 37 protein-metabolite relationships that were significant in a congruent fashion in both the observational and MR analyses were identified. A searchable online protein vs metabolite atlas was created for the scientific community to use these results. We also give some examples where metabolites were used to enhance protein findings in cardiovascular epidemiological research.

This study provides a comprehensive assessment of a large number of protein- metabolite relationships using both observational and MR analyses, highlighting how these results could be used to enhance clinical research.