Genome-wide Association Study for the Identification of Genetic Risk Factors of Periodontitis

Periodontitis (PD) is a chronic inflammatory disease of the oral mucosal barrier and the supporting tissues of the teeth. It is classified into the sub-forms chronic periodontitis (CP) and aggressive periodontitis (AgP). Whereas CP is mostly observed in adults and is characterized by a slow progress of the disease, AgP is found in young individuals and is diagnosed based on rapid attachment loss and destruction of the alveolar bone. Several environmental and life-style factors play a significant role in the aetiology of periodontitis, but these factors do not always lead to disease and there are susceptible and tolerant individuals. It is believed that genetic factors play a fundamental role in disease aetiology, particularly in the most severe phenotypes. The genetic basis of PD was demonstrated by formal genetic studies since many years but only a fraction of the heritability has yet been explained. Interestingly, coronary artery disease (CAD) and rheumatoid arthritis (RA) are associated with a higher incidence of PD, and it was suggested that PD may have some causal role. The objective of this research proposal is the elucidation of the genetic architecture of PD and the identification of genetic risk factors of PD, which are shared with CAD or RA. To this end, it is aimed to perform a genome-wide association study (GWAS) with 624 German AgP cases and existing GWAS data-sets of > 6,000 German controls using Illumina OmniExpess Arrays. Significant associations will be selected by genome-wide single-SNP association tests, gene-wide significance tests, and pathway analysis. We will further exploit readily available genotype-data sets of the custom genotyping array Exomechip (Illumina) for 600 German AgP cases and 3,000 German controls, and of various imputed genome-wide association study (GWAS) data sets of CAD and RA. Replication of selected significant SNP associations will be performed in an additional sample of further 600 European AgP cases and in an additional sample of Turkish AgP cases and controls. Replicated single nucleotide polymorphisms (SNPs) associations will be subsequently validated in a German sample of 1,200 CP cases and 2,500 controls. We further aim to identify the putative functional variants by targeted resequencing of selected regions that give the strongest evidence of association. Their role for disease aetiology will subsequently be validated in a large scale replication study in the complete AgP and CP case-control samples. The expected results will be important for the understanding of the disease relevant molecular pathways and for the development of new diagnostic tools and treatment modalities.

This research project conducted a GWAS and meta-analyses of PD and CAD to identify novel genetic risk variants. Four novel risk loci with genome-wide significance (P < 5 10E-08) were identified (DEFA1A3, SIGLEC5, LOC107964137, MTND1P5), and the associations of two additional loci were validated (VAMP8, PLG). In addition, the shared genetic basis of PD and CAD was confirmed and expanded. This study did not give evidence for a shared genetic basis of RA and T2D with PD. Furthermore, genotyping of 600 AgP cases and 6.940 German controls with the Illumina HumanExome chip 12v1 could not identify nonsynonymous PD risk alleles with large effect sizes. The identification and characterization of putative causative variants of PD is ongoing. CNV analyses for the copy number variable locus DEF1A3 suggested a single overrepresented haplotype that might increase PD risk. In current works, we are matching our SNP and CNV data and aim phasing the SNP and CNV haplotypes computationally. Additionally, we performed a G x S interaction study and give evidence that genetic variants at the genes SOST, SSH1, ST8SIA1, and BMP7 increase the disease susceptibility for AgP by interaction with cigarette smoke.