德国弗莱堡大学Anna Köttgen等人合作取得一项新突破。他们的最新研究利用代谢组学和外显子组测序，揭示了罕见破坏性杂合变异对基因功能和人类性状的不同影响。相关论文发表在2025年1月2日出版的《自然—遗传学》杂志上。

利用基于全外显子组测序数据的罕见变异聚合测试，检测与1,294种血浆和1,396种尿液代谢物水平相关的基因，研究人员发现了235种基因与代谢物的关联，其中许多以前从未报道过。互补方法（遗传、计算（在人体代谢全身模型中进行基因敲除）和一个实验性原理证明）提供了正交的证据，证明对杂合状态下罕见破坏性变异的研究，可以得出与先天性代谢错误一致的推论。

参与跨细胞硫酸盐重吸收转运体（SLC13A1、SLC26A1）的功能变体，对血浆硫酸盐和人的身高有不同程度的影响。研究还确定了与人群中各种肌肉骨骼特征，和疾病发生几率增加有关的等位基因。这种综合方法可以在特征不完全的人类代谢反应中发现新的成分，并揭示出与人类特征和疾病相关的代谢读数。

附：英文原文

Title: Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits

Author: Scherer, Nora, Fssler, Daniel, Borisov, Oleg, Cheng, Yurong, Schlosser, Pascal, Wuttke, Matthias, Haug, Stefan, Li, Yong, Telkmper, Fabian, Patil, Suraj, Meiselbach, Heike, Wong, Casper, Berger, Urs, Sekula, Peggy, Hoppmann, Anselm, Schultheiss, Ulla T., Mozaffari, Sahar, Xi, Yannan, Graham, Robert, Schmidts, Miriam, Kttgen, Michael, Oefner, Peter J., Knauf, Felix, Eckardt, Kai-Uwe, Grnert, Sarah C., Estrada, Karol, Thiele, Ines, Hertel, Johannes, Kttgen, Anna

Issue&Volume: 2025-01-02

Abstract: Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene–metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height and pinpointed alleles associated with increased odds of diverse musculoskeletal traits and diseases in the population. This integrative approach can identify new players in incompletely characterized human metabolic reactions and reveal metabolic readouts informative of human traits and diseases.

DOI: 10.1038/s41588-024-01965-7

Source: https://www.nature.com/articles/s41588-024-01965-7