Human and bacterial genetic variation shape oral microbiomes and health

Summary Paragraph Human genetic variation influences all aspects of our biology, including the oral cavity1–3, 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 dysbiosis3–5. 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement 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 were 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. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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. Yes 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Numerous changes throughout manuscript text, largely to shorten total length and make figures more compact. Additional significant analyses include comparison with standard microbiome taxa abundance GWAS, comparison with multivariate distance matrix regression, replication of gene dosage associations in All of Us cohort, and scan for other genetic effects on strongest dosage associations. Data availability 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/). To protect participant confidentiality, approved researchers can obtain access to the SPARK population dataset described in this study (SPARK integrated WGS (iWGS) v1.1) by applying at https://base.sfari.org. Quantifications of microbial abundances in SPARK generated in this study can also be obtained from SFARI Base. Summary statistics from genome-wide association analyses of microbial abundances in SPARK are available from the GWAS Catalog under accessions GCST90709872 to GCST90711133. Summary statistics from mPC-based GWAS of oral microbiome composition are available from Zenodo (https://doi.org/10.5281/zenodo.14559457; ref. 88). The following data resources are publicly available: Human Microbiome Project (https://hmpdacc.org/), human reference genome build GRCh38 (https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/reference/GRCh38_reference_genome/), MetaPhlAn vOct22 reference database (http://cmprod1.cibio.unitn.it/biobakery4/metaphlan_databases/), TOPMed-r3 imputation panel variant list (https://imputation.biodatacatalyst.nhlbi.nih.gov/), LD score resources (https://alkesgroup.broadinstitute.org/LDSCORE/), NCBI GenBank (https://www.ncbi.nlm.nih.gov/genbank/), and NCBI Conserved Domain Database (https://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml).