Host genetic control of the oral microbiome and its links to human metabolism and immunity

Host genetic influence on the oral microbiota, their functions, and associations with host phenotypes remain under investigated. Here, we present a large-scale genome-wide association study of the tongue dorsum microbiome in 13,397 Chinese participants from the CHARLS-4DSZ dataset, identifying ten genome-wide significant and replicated loci associated with 17 microbial taxa, eight pathways, and 1,783 gene families. The strongest signal maps to the missense variant FUT2 I140F, which regulates three taxa, with the most significant effect on Haemophilus sputorum (P = 9.71 × 10−51), and this association is independent of ABO blood groups. FUT2 is further associated with microbial D-arabinose degradation pathway and 134 gene families, including α-L-fucosidases and ABC transporters, implicating fucose-mediated host genetic regulation of microbial metabolism. Most identified microbiome-associated loci are functionally interpretable, affecting tissue/single-cell gene expression and linking to host immunometabolic traits: the POLI locus associates with Haemophilus parahaemolyticus and influences white blood cell counts and triglyceride levels, while SLC2A9 (urate transporter) regulates serum uric acid and uric acid-degrading bacteria harboring uric acid-utilizing gene clusters. Additionally, 239 significant associations are observed between 94 microbial features and 43 host phenotypes. Mendelian randomization further confirms eleven causal relationships, including microbial effects on blood gamma-glutamyl transferase, creatine, and uric acid, suggesting microbial roles in the host liver and kidney metabolism. Together, our study provides a comprehensive map of oral microbiome genetics, advancing mechanistic understanding of host-microbe interactions.