Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

Abstract

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

Genomics of periodontal disease and tooth morbidity

“…A prime example is SIGLEC5 (rs12461706), which was reported in a recent study of aggressive periodontitis 30 and was the only locus that met genome-wide statistical significance criteria in a large, consortium meta-analysis of chronic periodontitis that combined clinical and self-reported data. 31 In a recent Korean study, Hong et al 25 30 and an earlier chronic periodontitis study. 29 NPY is another locus of interest.…”

“…Additional loci not meeting genome‐wide significance criteria but with multiple lines of supporting evidence requiring some attention, include MMP16 (rs2046315 and rs10429371), PKD2 (rs17013735, rs11938025, rs2725270) and SIBLING (rs2725233), MPPED2 and ACTN2, and TRAV4 . Although additional insights have been gained by gene set enrichment re‐analyses of a dental caries genome‐wide association study reported by Wang et al, the recent, large‐scale consortium meta‐analysis that included clinical and self‐reported data (including denture use) among half a million individuals, discovered 47 novel loci for adult dental caries …”

Inference and visualization of phenome-wide causal relationships using genetic data: an application to dental caries and periodontitis

“…One example is Mendelian Randomization (MR), an analytical paradigm which uses genetic variants as proxies for a risk factor in order to test for causal effects on an outcome 7 . In dental epidemiology, this method has been used to examine the effects of potentially modifiable risk factors like Vitamin D and body mass index on caries and periodontitis 8,9 , to assess the possible impact of periodontitis on hypertension 10 and undertake bi-directional analysis to test for causal relationships between dental diseases and cardio-metabolic traits in both directions 11 . To date, these studies have only explored a small number of traits and the bespoke experimental design used for each study makes it difficult to compare estimates for different diseases.…”

“…It can be difficult to distinguish this from horizontal pleiotropy, where a genetic variant has biological effects on both trait A and trait B. Many genetic variants have horizontally pleiotropic effects, leading to false positive findings or over-estimation in effect sizes at true positive associations in classical MR experiments 11,12 . Several estimation techniques have been developed which use the distribution of causal effect estimates across multiple variants in an attempt to detect and account for [13][14][15] or at least reduce the impact of horizontal pleiotropy 16 .…”

“…Here we introduce CTG-VL's newly implemented capability to perform a phenome-wide scan across hundreds of traits using the LCV method and the visualization of the results using causal architecture plots. We showcase this method using GWAS data for body mass index, lipid levels, dental caries and periodontitis 11 .…”