血清代谢基因组关联研究（GWASs）具有揭示影响人类代谢的基因潜能。在这里，我们将血清代谢物与膜转运体相关的综合遗传分析与代谢基因中的协同本质联系图结合起来后发现了猫白血病病毒C亚族细胞受体1（FLVCR1）和磷酸胆碱之间的联系是胆碱代谢的下游代谢产物。由于胆碱进口的抑制，FLVCR1在人类细胞中缺失会严重影响胆碱代谢。一致地，基于CRISPR的遗传筛查确定了磷脂合成和拯救机器与FLVCR1的损失合成致死。缺乏FLVCR1的细胞和小鼠显示出线粒体结构缺陷，并通过血红素调节抑制物（HRI）激酶上调整合应激反应（ISR）。最后，Flvcr1敲除小鼠在胚胎期就会死亡，通过胆碱的补充部分得到临时解救。总之，我们的发现表明FLVCR1是哺乳动物中的主要胆碱转运体，并提供一个平台来发现未知代谢物转运体的底物。Copyright © 2023 Elsevier Inc. All rights reserved.

Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis that associates serum metabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) and phosphocholine, a downstream metabolite of choline metabolism. Loss of FLVCR1 in human cells strongly impairs choline metabolism due to the inhibition of choline import. Consistently, CRISPR-based genetic screens identified phospholipid synthesis and salvage machinery as synthetic lethal with FLVCR1 loss. Cells and mice lacking FLVCR1 exhibit structural defects in mitochondria and upregulate integrated stress response (ISR) through heme-regulated inhibitor (HRI) kinase. Finally, Flvcr1 knockout mice are embryonic lethal, which is partially rescued by choline supplementation. Altogether, our findings propose FLVCR1 as a major choline transporter in mammals and provide a platform to discover substrates for unknown metabolite transporters.Copyright © 2023 Elsevier Inc. All rights reserved.