AUTHOR=Yu Yau-Hua , Steffensen Bjorn , Ridker Paul M. , Buring Julie E. , Chasman Daniel I. 

TITLE=Candidate loci shared among periodontal disease, diabetes and bone density

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1016373

DOI=10.3389/fendo.2022.1016373

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>While periodontal disease (PD) has been associated with type 2 diabetes (T2D) and osteoporosis, the underlying genetic mechanisms for these associations remain largely unknown. The aim of this study is to apply cross-trait genetic analyses to investigate the potentially shared biology among PD, T2D, and bone mineral density (BMD) by assessing pairwise genetic correlations and searching for shared polymorphisms.</p></sec><sec><title>Methods</title><p>We applied cross-trait genetic analyses leveraging genome-wide association study (GWAS) summary statistics for: Periodontitis/loose teeth from the UKBB/GLIDE consortium (PerioLT, N=506594), T2D from the DIAGRAM consortium (N<sub>eff</sub>=228825), and BMD from the GEFOS consortium (N=426824). Among all three, pair-wise genetic correlations were estimated with linkage disequilibrium (LD) score regression. Multi-trait meta-analysis of GWAS (MTAG) and colocalization analyses were performed to discover shared genome-wide significant variants (p<sub>MTAG</sub> &lt;5x10<sup>-8</sup>). For replication, we conducted independent genetic analyses in the Women’s Genome Health Study (WGHS), a prospective cohort study of middle-aged women of whom 14711 provided self-reported periodontal disease diagnosis, oral health measures, and periodontal risk factor data including incident T2D.</p></sec><sec><title>Results</title><p>Significant genetic correlations were identified between PerioLT/T2D (Rg=0.23; SE=0.04; p=7.4e<sup>-09</sup>) and T2D/BMD (Rg=0.09; SE=0.02; p=9.8e<sup>-06</sup>). Twenty-one independent pleiotropic variants were identified <italic>via</italic> MTAG (p<sub>MTAG</sub>&lt;5x10<sup>-8</sup> across all traits). Of these variants, genetic signals for PerioLT and T2D colocalized at one candidate variant (rs17522122; Prob<sub>H4 =</sub> 0.58), a 3’UTR variant of <italic>AKAP6</italic>. Colocalization between T2D/BMD and the original PerioLT GWAS p-values suggested 14 additional loci. In the independent WGHS sample, which includes responses to a validated oral health questionnaire for PD surveillance, the primary shared candidate (rs17522122) was associated with less frequent dental flossing [OR(95%CI)= 0.92 (0.87-0.98), p=0.007], a response that is correlated with worse PD status. Moreover, 4 additional candidate variants were indirectly supported by associations with less frequent dental flossing [rs75933965, 1.17(1.04-1.31), p=0.008], less frequent dental visits [rs77464186, 0.82(0.75-0.91), p=0.0002], less frequent dental prophylaxis [rs67111375, 0.91(0.83-0.99), p=0.03; rs77464186, 0.80(0.72-0.89), p=3.8e<sup>-05</sup>], or having bone loss around teeth [rs8047395, 1.09(1.03-1.15), p=0.005].</p></sec><sec><title>Discussion</title><p>This integrative approach identified one colocalized locus and 14 additional candidate loci that are shared between T2D and PD/oral health by comparing effects across PD, T2D and BMD. Future research is needed to independently validate our findings.</p></sec>