美国范德堡大学医学中心Eric R. Gamazon、洛克菲勒大学K?vanç Birsoy课题组报道，代谢基因功能发现平台GeneMAP鉴定出SLC25A48是线粒体胆碱输入所必需的。该研究于2024年7月8日发表于国际一流学术期刊《自然—遗传学》杂志上。

研究人员利用大规模血浆代谢组全基因组关联研究(GWAS)，来开发多组基因-代谢物关联预测(GeneMAP)发现平台。GeneMAP可以产生准确的预测，甚至可以确定与GWAS所涉及的变异距离较远的基因。特别是，他们的分析确定了溶质载体家族25成员48 (SLC25A48)是血浆胆碱水平的遗传决定因素。从机制上说，SLC25A48的缺失严重损害了线粒体胆碱的进入及其下游代谢物甜菜碱的合成。

英国生物银行(UK Biobank)的综合罕见变异和多基因评分分析提供了强有力的证据，表明SLC25A48对人类的致癌作用可能部分由胆碱的作用介导。总之，他们的研究为代谢基因功能提供了一个发现平台，并提出SLC25A48是线粒体胆碱转运蛋白。

据了解，生物体通过小分子转运体和酶的联合作用维持代谢稳态。虽然许多代谢成分已经很好地建立起来，但仍有相当数量的代谢成分没有确定的生理底物。

附：英文原文

Title: Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import

Author: Khan, Artem, Unlu, Gokhan, Lin, Phillip, Liu, Yuyang, Kilic, Ece, Kenny, Timothy C., Birsoy, Kvan, Gamazon, Eric R.

Issue&Volume: 2024-07-08

Abstract: Organisms maintain metabolic homeostasis through the combined functions of small-molecule transporters and enzymes. While many metabolic components have been well established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene–Metabolite Association Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions and even pinpoint genes that are distant from the variants implicated by GWAS. In particular, our analysis identified solute carrier family 25 member 48 (SLC25A48) as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite betaine. Integrative rare variant and polygenic score analyses in UK Biobank provide strong evidence that the SLC25A48 causal effects on human disease may in part be mediated by the effects of choline. Altogether, our study provides a discovery platform for metabolic gene function and proposes SLC25A48 as a mitochondrial choline transporter.

DOI: 10.1038/s41588-024-01827-2

Source: https://www.nature.com/articles/s41588-024-01827-2