Human and bacterial genetic variation shape oral microbiomes and health

Summary Paragraph Human genetic variation influences all aspects of our biology, including the oral cavity 1–3 , through which nutrients and microbes enter the body. Yet it is largely unknown which human genetic variants shape a person’s oral microbiome and potentially promote its dysbiosis 3–5 . We characterized the oral microbiomes of 12,519 people by re-analyzing whole-genome sequencing reads from previously sequenced saliva-derived DNA. Human genetic variation at 11 loci (10 novel) associated with variation in oral microbiome composition. Several of these related to carbohydrate availability; the strongest association ( p =3.0×10 −188 ) involved the common FUT2 W154X loss-of-function variant, which associated with the abundances of 58 bacterial species. Human host genetics also appeared to powerfully shape genetic variation within oral bacterial species: these 11 host genetic variants also associated with variation of gene dosages in 68 regions of bacterial genomes. Common, multi-allelic copy-number variation of AMY1 , which encodes salivary amylase, associated with oral microbiome composition ( p =1.5×10 −53 ) and with dentures use in UK Biobank ( p =5.9×10 −35 , n=418,039) but not with body mass index ( p =0.85), suggesting that amylase abundance impacts health by influencing the oral microbiome. Two other microbiome composition-associated loci, FUT2 and PITX1 , also significantly associated with dentures risk, collectively nominating numerous host-microbial interactions that contribute to tooth decay.