Genome- and Transcriptome-Wide Association Studies Identify Susceptibility Genes and Pathways for Periodontitis

Several genes associated with periodontitis have been identified through genome-wide association studies (GWAS); however, known genes only explain a minority of the estimated heritability. We aimed to explore more susceptibility genes and the underlying mechanisms of periodontitis. Firstly, a genome-wide meta-analysis of 38,532 patients and 316,185 healthy controls was performed. Then, cross- and single-tissue transcriptome-wide association studies (TWAS) were conducted based on GWAS summary statistics and the Genotype-Tissue Expression (GTEx) project. Risk genes were evaluated to determine if they were differentially expressed in periodontitis sites compared with unaffected sites using public datasets. Finally, gene co-expression network analysis was conducted to identify the functional biology of the susceptible genes. A total of eight single nucleotide polymorphisms (SNPs) within the introns of lncRNA LINC02141 approached genome-wide significance after meta-analysis. EZH1 was identified as a novel susceptibility gene for periodontitis by TWAS and was significantly upregulated in periodontitis-affected gingival tissues. EZH1 co-expression genes were greatly enriched in the cell-substrate junction, focal adhesion and other important pathways. Our findings may offer a fundamental clue for comprehending the genetic mechanisms of periodontitis.

Automated summary

Several genes associated with periodontitis have been identified, but known genes explain only a small percentage of the heritability. This study aimed to explore more susceptibility genes and the underlying mechanisms of periodontitis. A genome-wide meta-analysis and transcriptome-wide association studies were conducted, and a novel susceptibility gene EZH1 was identified. EZH1 was upregulated in periodontitis-affected gingival tissues, and its co-expression genes were enriched in important pathways. These findings provide a fundamental clue for understanding the genetic mechanisms of periodontitis.