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代谢组学与外显子组测序相结合揭示了罕见有害杂合变异对基因功能和人类性状的分级影响。

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

作者信息

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

机构信息

Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.

Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.

出版信息

Nat Genet. 2025 Jan;57(1):193-205. doi: 10.1038/s41588-024-01965-7. Epub 2025 Jan 2.

DOI:
10.1038/s41588-024-01965-7
PMID:39747595
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11735408/
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.

摘要

代谢组的遗传学研究能够揭示塑造人类新陈代谢的酶促过程和转运过程。利用基于全外显子组测序数据的罕见变异聚集测试来检测与1294种血浆代谢物和1396种尿液代谢物水平相关的基因，我们发现了235个基因-代谢物关联，其中许多关联此前未被报道。互补方法（遗传学、计算方法（在人类新陈代谢的全身模型中进行计算机模拟基因敲除）以及一个原理性实验证据）提供了正交证据，表明对杂合状态下罕见的有害变异进行研究能够得出与先天性代谢缺陷研究一致的推断。负责跨细胞硫酸盐重吸收的转运蛋白（SLC13A1、SLC26A1）中的功能性变异等位基因系列对血浆硫酸盐和人类身高表现出分级效应，并确定了与人群中各种肌肉骨骼性状和疾病几率增加相关的等位基因。这种综合方法能够识别在特征不完全明确的人类代谢反应中的新参与者，并揭示与人类性状和疾病相关的代谢读数。

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