ArticleNature genetics2025
Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits.
Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Deviations from genetic additivity driven by rare variants at biobank scale.Nature communications · 2026Article
- X-chromosomal genetic variants and haplotype analysis in male cerebral palsy patients: insights into genetic susceptibility and sex-specific risk.Journal of neurodevelopmental disorders · 2026Article
- Analysis of whole genome sequencing and plasma metabolomics unveil genetic determinants and clinical implications for human health.Nature communications · 2026Article
- Genetic architecture of plasma metabolome in 254,825 individuals.Nature communications · 2025Article
- Genetic determinants of urine and plasma metabolite levels.Nature reviews. Nephrology · 2025Article
- A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.Journal of inherited metabolic disease · 2025Article
- Panera: An innovative framework for surmounting uncertainty in microbial community modeling using pan-genera metabolic models.iScience · 2024Article
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Authors and funding
29 authors.
Funding
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.
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Registered trials
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