Genome-wide association study identifies novel risk loci for apical periodontitis.

Apical periodontitis (AP) is a common consequence of root canal infection leading to periapical bone resorption. Microbial and host genetic factors, and their interactions, have been shown to play a role in AP development and progression. Variations in a few genes have been reported in association with AP, however, the lack of genome-wide studies has hindered progress in understanding the mechanisms involved in AP. Here, we report the first genome-wide association study of AP in a well-characterized population. Male and female adults (n=932) presenting with deep caries with AP (cases) or without AP (controls) were included. Genotyping was performed using the Illumina Expanded Multi-Ethnic Genotyping Array. Single-variant association testing was performed adjusting for sex and five principal components. Subphenotype association testing, analyses of genetically regulated gene expression, polygenic risk score and phenome-wide association (PheWAS) analyses were also performed. Eight loci reached near-genome-wide significant association with AP (p < 5 x 10-6); gene-focused analyses replicated three previously reported associations (p < 8.9 x 10-5). Sex-specific and subphenotype analyses revealed additional significant associations with variants genome-wide. Functionally oriented gene-based analyses revealed eight genes significantly associated with AP (p < 5 x 10-5), and PheWAS analysis revealed 33 phecodes associated with AP risk score (p < 3.08 x 10-5). This study identified novel genes/loci contributing to AP and revealed specific contributions to AP risk in males and females. Importantly, we identified additional systemic conditions significantly associated with AP risk. Our findings provide strong evidence for host-mediated effects on AP susceptibility.

Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.