Microbiome-wide PheWAS links gut microbial SNVs to health and exposures.

Alterations in the microbial composition of the human gut have been associated with a wide range of chronic diseases. Yet species-level composition alone can obscure extensive within-species genetic diversity and functional variation. This has driven a shift towards strain-resolved, genetic-level analysis of the microbiome, leveraging microbial genetic variation to identify disease-relevant genes and pathways. Here we conducted a phenome-wide association study (PheWAS) analysing 12.8 million gut microbial single-nucleotide variants (SNVs) with 244 host health phenotypes and environmental exposures in 10,781 individuals from 6 independent cohorts. We identify 940 independent associations across 69 host factors, including age, sex and cardiovascular and metabolic parameters. Structural analyses identified host-phenotype-associated SNVs in functionally important regions of proteins, findings that inform mechanistic hypotheses about how microbial genetic changes relate to environmental and host physiological factors. For example, we identified an age-associated SNV in Faecalibacterium prausnitzii that affects an amino acid within the protein pocket that binds glutathione. To support future efforts, all study summary statistics are provided in an online catalogue ( https://fulab.web.rug.nl/SNV-MWAS/ ). Together, these results identify new biological connections between the human host and microbial genetic variants at base pair resolution and provide a resource for hypothesis generation that will aid future understanding of the strain-level functionality of the gut microbiota.

© 2026. The Author(s).

PMID: 42983083