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 underpinnings 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 participants with generated untargeted metabolomics data to identify metabolite quantitative trait loci (mQTL) 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 donations in the past two years, and first ten 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 associations 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 polymorphisms was validated in an independent cohort and novel murine models of G6PD deficiency (African and Mediterranean variants). We demonstrate that it is possible to perform metabolomics-scale GWA analyses with a modest, trans-ancestry sample size.

红细胞 (RBC)-组学研究是更大的 NHLBI 资助的接受者流行病学和供体评估研究 (REDS-III) 的一部分，旨在了解遗传对献血者红细胞特征的贡献。之前的工作确定了献血者的人口统计、行为、遗传和代谢基础与献血、储存和（在较小程度上）输血结果有关，但还没有人将遗传和代谢工作联系起来。我们使用 RBC-Omics 研究参与者和生成的非靶向代谢组学数据进行了全基因组关联 (GWA) 分析，以确定 RBC 中的代谢物数量性状位点 (mQTL)。我们对使用 1000 基因组计划第 3 阶段全血统参考面板估算的 243 个个体的 382 种代谢物进行了 GWA 分析。使用 ProbABEL 进行分析，并针对性别、年龄、献血中心、近两年全血献血次数、血统前十个主成分。我们的结果确定了与 132 种代谢物相关的 423 个独立基因位点 (p < 5x10-8)。为编码血红素转运蛋白 FLVCR1 和胆碱的区域以及溶血磷脂酰胆碱乙酰转移酶 LPCAT3 和溶血磷脂酰丝氨酸 16.0、18.0、18.1 和 18.2 确定了潜在的新基因座-代谢物关联；这些关联得到了已发表的罕见病和小鼠研究的支持。我们还证实了先前代谢物 GWA 结果的相关性，包括 N(6)-甲基-L-赖氨酸和蛋白质 PYROXD2，以及各种肉毒碱和转运蛋白 SLC22A16。丙酮酸水平与 G6PD 多态性之间的关联在独立队列和 G6PD 缺乏症（非洲和地中海变体）的新型小鼠模型中得到验证。我们证明可以使用适度的跨血统样本量进行代谢组学规模的 GWA 分析。