Genomic landscape of the human vaginal microbiome is linked to host genetics and population of origin

The vaginal microbiome is essential for women’s health, yet its genomic diversity and interaction with the host remain incompletely characterized. Here we present the Global Vaginal Metagenome-assembled Genomes catalog, an extensive repository of vaginal microbial genomes generated by integrating 10,665 in-house Chinese metagenomes, with 2,967 publicly available metagenomes and 1,433 bacterial isolates. The catalog comprises 65,055 genomes from 890 prokaryotes, 11 eukaryotes and 6,590 viral taxonomic units, many not represented in public reference databases. We investigate virus–bacteria interactions, revealing conserved phages–host associations. We then identify substantial intraspecies genomic and functional variations displaying population-specific patterns. A metagenome-genome-wide association study identifies seven host genetic loci associated with vaginal species at study-wide significance and replicated in at least one independent cohort, notably connecting the gene OPRK1 with the potential pathogen Ureaplasma urealyticum. In summary, our research provides a comprehensive reference for future studies on genotype–phenotype interplay within the human vaginal microbiome. Metagenomics, coupled with genome-wide association analyses, highlights population-specific patterns of variation within the vaginal microbiome and identifies host genetic loci associated with vaginal microbiome composition.