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

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) exhibit

SUBMITTER: Scherer N 

PROVIDER: S-EPMC11735408 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature