ArticleeLife2022
Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pooled it
- Review
- Genetic architectures of brain-related traits are shaped by strong selective constraints.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Allele frequencies at recessive disease genes are mainly determined by pleiotropic effects in heterozygotes.Genetics · 2026Article
- Genetic architectures of brain-related traits are shaped by strong selective constraints.bioRxiv : the preprint server for biology · 2026Article
- Plant-based diet, metabolic signature, genetic susceptibility, and risk of musculoskeletal disorders: a large-scale population-based prospective cohort study.Frontiers in public health · 2026Article
- Article
- Allele Frequencies at Recessive Disease Genes are Mainly Determined by Pleiotropic Effects in Heterozygotes.bioRxiv : the preprint server for biology · 2025Article
- Adiposity, metabolites and endometrial cancer risk: inference from combinations of Mendelian randomization and observational analyses.BMC cancer · 2025Observational
- A genetic map of human metabolism across the allele frequency spectrum.Nature genetics · 2025Article
- Article
- Haplotype analysis reveals pleiotropic disease associations in the HLA region.American journal of human genetics · 2025Article
- Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers.Nature communications · 2025Article
- Genome-wide association study for circulating metabolic traits in 619,372 individuals.medRxiv : the preprint server for health sciences · 2025Article
- Understanding genetic variants in context.eLife · 2024Article
- Quantitative omnigenic model discovers interpretable genome-wide associations.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Healthy Lifestyle, Metabolic Signature, and Risk of Cardiovascular Diseases: A Population-Based Study.Nutrients · 2024Article
- Epistasis and pleiotropy-induced variation for plant breeding.Plant biotechnology journal · 2024Review
- Haplotype Analysis Reveals Pleiotropic Disease Associations in the HLA Region.medRxiv : the preprint server for health sciences · 2024Article
- Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.BMC medicine · 2024Article
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Authors and funding
7 authors.
Funding
Abstract
Pleiotropy and genetic correlation are widespread features in genome-wide association studies (GWAS), but they are often difficult to interpret at the molecular level. Here, we perform GWAS of 16 metabolites clustered at the intersection of amino acid catabolism, glycolysis, and ketone body metabolism in a subset of UK Biobank. We utilize the well-documented biochemistry jointly impacting these metabolites to analyze pleiotropic effects in the context of their pathways. Among the 213 lead GWAS hits, we find a strong enrichment for genes encoding pathway-relevant enzymes and transporters. We demonstrate that the effect directions of variants acting on biology between metabolite pairs often contrast with those of upstream or downstream variants as well as the polygenic background. Thus, we find that these outlier variants often reflect biology local to the traits. Finally, we explore the implications for interpreting disease GWAS, underscoring the potential of unifying biochemistry with dense metabolomics data to understand the molecular basis of pleiotropy in complex traits and diseases.
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