Periodontitis is a multifactorial inflammatory disease whose pathogenesis is associated with intricate interactions between genetic and environmental factors. Leveraging electronic health records data from the All of Us Research Program, we stratified periodontitis by clinically relevant dimensions: stage, grade, and extent. Based on these phenotypes, we performed a multi-ancestry genome-wide association study, focusing on predominant ancestry populations of African, European, and Admixed American. Our study cohort comprised 3,881 periodontitis patients and a control group of 10,760 patients with dental caries and without periodontitis. Ancestry-specific GWAS revealed significant genetic associations (P<5x10-8) in periodontitis grade phenotypes at the LINC00294 and CLMN loci in the African ancestry population and also confirmed via the multi-ancestry meta-analysis. In addition, the XYLT1 locus emerged as a significant signal associated with periodontitis grade phenotype in the admixed American GWAS. Our GWAS comparing periodontitis to dental caries in the admixed American population identified several significant loci, including RABGAP1L, previously linked to immune regulation, DCHS2, a cadherin-related gene involved in bone mineralization and tissue morphogenesis, and OSTM1, known to be crucial for bone remodeling. The findings of our study highlight the potential of integrating EHR and genomic data from large-scale biobanks to achieve informative dental phenotyping, uncover novel molecular insights into periodontal disease, and personalize treatment approaches.

The authors have declared no competing interest.

Research reported in this publication was supported by the National Library of Medicine of the National Institutes of Health under Award Number R01LM014249, and by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI175699. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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

The All of Us protocol was reviewed and approved by the Institutional Review Board (IRB) of the All of Us Research Program (2021-02-TN-001). The All of Us IRB follows the regulations and guidance of the NIH Office for Human Research Protections for all studies, ensuring that the rights and welfare of research participants are overseen and protected uniformly. The present study did not directly involve participants, only their data; and the data available in the Researcher Workbench has been carefully checked and altered to remove identifying information while preserving its scientific utility. The Researcher Workbench employs a data passport model, through which authorized users do not need IRB review for each research project. As such, this research is considered non-human subjects research, and project-specific IRB approvals or waivers are not required. In compliance with the All of Us Data and Statistics Dissemination Policy, no results that include fewer than 20 participants are reported, in order to protect participant privacy.

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