Despite significant improvement in treating periodontal disease (PD) and the identification of multiple risk factors, little is known about the specific contribution of genetics to PD pathogenesis. Several genome- wide association studies (GWAS) of PD have been published, but only one reported locus has reached the threshold for genome-wide significance. Epidemiological studies and biological experiments established associations and suggested common pathogenetic pathways between PD and cardiovascular disease (CVD), diabetes (DM), and osteoporosis. The overall objective is to identify genetic loci for PD as a first step toward a better understanding of PD pathogenesis. In a preliminary study in the Women's Genome Health Study (WGHS), new-onset cases of PD were associated with a family history of myocardial infarction (MI). Further preliminary analyses presented shared phenotypic variation of PD/CVD, PD/DM, or PD/osteoporosis that could be accounted by the whole-genome genetic matrices. Several variants from the GWAS catalog of bone density and family history of MI were found correlated with PD in the WGHS. Based on these findings and the literature, the central hypothesis is that there are common pathogenetic links between PD and these other diseases and that GWAS using the comorbidity case definitions will help identify potential common loci. Three specific aims independently refine the approach to GWAS of PD: (1) Validate and expand the PD information by adding the CDC-AAP self-reported periodontal parameters to the annual follow-up survey in the Women's Health Study; (2) Identify genetic determinants of PD shared with CVD, DM, or osteoporosis via an integrative computational biological networks approach; and (3) Preparatory training to connect and collaborate with future large dental-genomic databases for GWAS of PD. These aims also provide a mentored training experience for Dr. Yau-Hua Yu, a talented dentist scientist with a strong background in periodontology and bioinformatics. Dr. Yu's career goal is to integrate epidemiological, genomic and clinical studies to elucidate the systemic links and genetic components that periodontal disease shares with cardiovascular disease, diabetes and osteoporosis. Given the administrative and analytical complexity of this intended research path, her training goal is to acquire skills and experience in the following areas: 1) Data collection, analysis, interpretation and validation studies for self-reported outcomes. 2) Management, quantitative analysis and interpretation of large-scale genetic epidemiological datasets across multiple sites and technological platforms. 3) Accession, integration and interpretation of high- dimensional data-rich bioinformatics resources to enrich prior and develop new hypotheses. Dr. Yu and her mentor, Dr. Bjorn Steffensen, have assembled a team of advisors who are experts in their fields as well as leaders of the large cohort studies required for the proposed work. The proposed work will highlight future research paths for PD and open possible new avenues of investigation for comorbid conditions.

Periodontal disease (PD) affects about 46% of the adult population in the US, and about 8.9% have a severe form, which is difficult to treat and highly correlated with other comorbid systemic conditions such as cardiovascular disease, diabetes, and osteoporosis. Although it is estimated from twin studies that approximately 50% of the risk for chronic periodontitis is genetic, as of today, only one genetic determinant of PD has been identified significant using the genome-wide approach. This study aims to identify genetic determinants for PD through three different approaches in the genome-wide association study (GWAS) setting: (1) expanding new PD data by adding self-reported CDC-AAP periodontal health questions; (2) conducting GWAS and GWAS meta-analysis by using comorbid case definitions (having PD and a family history of myocardial infarction, or diabetes, or osteoporosis), integrating biological knowledge from different levels and pathways; and (3) by preparatory training and learning to develop a dental-genomic collaboration platform for future studies.