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 PITX, also significantly associated with dentures risk, collectively nominating numerous microbial taxa that might contribute to tooth decay.

The authors have declared no competing interest.

N.K. was supported by US NIH Fellowship F31 DE034283. R.E.H. and S.A.M. were supported by US NIH grant R01 HG006855. M.L.A.H. was supported by US NIH Fellowship F32 HL160061. R.E.M. was supported by US NIH grant K25 HL150334. S.A.M. was supported by the Howard Hughes Medical Institute. P.-R.L. was supported by US NIH grants R56 HG012698 and R01 HG013110 and a Burroughs Wellcome Fund Career Award at the Scientific Interfaces. The funders had no role in study design, data collection and analysis, the decision to publish or the preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Computational analyses were performed on the O2 High Performance Compute Cluster supported by the Research Computing Group at Harvard Medical School (http://rc.hms.harvard.edu), the UKB Research Analysis Platform, and the All of Us Researcher Workbench. Molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. The All of Us Research Program is supported by the NIH, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA no. AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center:5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; and 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

North West-Haydock Research Ethics Committee gave ethical approval for UK Biobank data collection and availability under reference 16/NW/0274. Western IRB of Wayne State University gave ethical approval for Simons Foundation Autism Research Initiative (SPARK) data collection and availability under protocol 20151664. The Office of Research Subject Protection (ORSP) of the Broad Institute waived ethical approval for this work, as this research on de-identified, previously-collected data was determined not to constitute human subjects research and did not require IRB review. Data from the UKB Resource were accessed under application number 40709.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The following data resources are available by application: UKB (http://www.ukbiobank.ac.uk/), All of Us Research Program (https://allofus.nih.gov/), and SFARI SPARK (https://www.sfari.org/resource/spark/). The following data resource is publicly available: Human Microbiome Project (https://hmpdacc.org/). Relative abundances of species in the oral microbiome will be returned to SFARI for release upon request.