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Rare Genetic Variants Affecting Urine Metabolite Levels Link Population Variation to Inborn Errors of Metabolism
Yurong Cheng
Pascal Schlosser
Johannes Hertel
Peggy Sekula
Peter J. Oefner
Ute Spiekerkötter
Johanna Mielke
Daniel Freitag
Miriam Schmidts
Florian Kronenberg
Kai-Uwe Eckardt
Ines Thiele
Yong Li
Anna Köttgen
[Study Group] German Chronic Kidney Disease
出版
Universität
, 2021
URL
http://books.google.com.hk/books?id=fgZuzgEACAAJ&hl=&source=gbs_api
註釋
Abstract: Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e−7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism