Human and bacterial genetic variation shape oral microbiomes and health

It is largely unknown which human genetic variants shape a person's oral microbiome and potentially promote its dysbiosis. We characterized the oral microbiomes of 12,519 people by analyzing whole-genome sequencing reads from previously sequenced saliva-derived DNA. Human genetic variation at 11 loci (10 novel) associated with differences in oral microbiome composition. Nearly all of these associations implicated candidate genes with readily interpretable functions, several related to carbohydrate availability. The strongest association ( p =3.0x10 ^-188 ) involved the common FUT2 W154X loss-of-function variant, which associated with the abundances of 32 bacterial species. Human host genetics also appeared to powerfully shape within-species genetic variation in oral bacteria. Variation at the 11 human loci associated with variation in gene dosages in 68 regions of bacterial genomes. Several such associations implicated interactions of bacterial proteins with histo-blood group antigens presented on host mucosal cell surfaces and salivary proteins. Common, multi-allelic copy-number variation of AMY1 , which encodes salivary amylase, associated with oral microbiome composition ( p =1.5x10 ^-53 ) and with dentures use in UK Biobank ( p =5.9x10 ^-35 , n=418k), suggesting that amylase abundance impacts oral health by influencing the oral microbiome. Two other microbiome composition-associated loci, FUT2 and PITX1 , also significantly associated with dentures risk, collectively nominating numerous microbial taxa that might contribute to tooth decay.