Genome-wide metabolite quantitative trait loci analysis (mQTL) in red blood cells from volunteer blood donors

The red blood cell (RBC)-Omics study, part of the larger NHLBI-funded Recipient Epidemiology and Donor Evaluation Study (REDS-III), aims to understand the genetic contribution to blood donor RBC characteristics. Previous work identified donor demographic, behavioral, genetic, and metabolic un-derpinnings to blood donation, storage, and (to a lesser extent) transfusion outcomes, but none have yet linked the genetic and metabolic bodies of work. We performed a genome-wide association (GWA) analysis using RBC-Omics study partici-pants with generated untargeted metabolomics data to iden-tify metabolite quantitative trait loci in RBCs. We performed GWA analyses of 382 metabolites in 243 individuals imputed using the 1000 Genomes Project phase 3 all-ancestry reference panel. Analyses were conducted using ProbABEL and adjusted for sex, age, donation center, number of whole blood dona-tions in the past 2 years, and first 10 principal components of ancestry. Our results identified 423 independent genetic loci associated with 132 metabolites (p < 5x10-8). Potentially novel locus-metabolite associations were identified for the region encoding heme transporter FLVCR1 and choline and for lysophosphatidylcholine acetyltransferase LPCAT3 and lysophosphatidylserine 16.0, 18.0, 18.1, and 18.2; these asso-ciations are supported by published rare disease and mouse studies. We also confirmed previous metabolite GWA results for associations, including N(6)-methyl-L-lysine and protein PYROXD2 and various carnitines and transporter SLC22A16. Association between pyruvate levels and G6PD poly-morphisms was validated in an independent cohort and novel murine models of G6PD deficiency (African and Mediterra-nean variants). We demonstrate that it is possible to perform metabolomics-scale GWA analyses with a modest, trans -ancestry sample size.

Automated summary

The RBC-Omics study aims to understand the genetic contribution to blood donor RBC characteristics. Through genome-wide association analysis, multiple genetic loci associated with metabolites were identified, including potentially novel associations.