Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci

Abstract

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10^-9, OR = 1.36, 95% CI = [1.23-1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10^-9, OR = 1.24, 95% CI = [1.15-1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.

Fig. 1

Description of the analysis workflow. a A two-step meta-analysis was performed because for the German CP case-control sample (SHiP cohort), the complete GWAS dataset was not available to be directly included into the meta-analysis. Thus, in the first step, hypotheses on candidate gene regions were generated with the genome-wide summary statistics of the N.-W.-EU AgP-GWAS and the EU-USA CP-GWAS data alone. Next, genotypes of the priorized candidate risk loci were obtained from the SHiP cohorts and included into the dataset of the first meta-analysis. This gave the validation meta-analysis dataset, which provided the highest statistical power. This increase in statistical power resulted in genome-wide significance of two loci. (N.W. EU North-West Europeans, EU-USA European-US Americans, NL The Netherlands, PD Periodontitis, AgP Aggressive Periodontitis). b In small sample sizes such as the Dutch AgP case sample, chance effects are immanent and can skew the results, e.g., by random depletion of risk alleles in a particular sample. The misrepresentation of the allele frequency in a small case sample can have strong effects on the inter sample heterogeneity. However, a low inter sample heterogeneity is the prerequisite for applying the fixed effects model in which the effects of each study sample are weighted by the sample size. Otherwise the random effects model must be applied in which all study samples are weighted equally, irrespective of the sample size. Therefore, the two-step meta-analysis of a was repeated without the Dutch AgP case-control sample. In this analysis, we re-discovered the association of SNP rs729876 with an equal association P-value. Additionally, a second association of SNP rs16870060 passed the genome-wide significance threshold (P = 5 × 10E-08)

Fig. 2

Regional association plots of the identified loci with P < 10⁻⁶ for the lead variants. Due to the low number of variants that were existent in all samples, this plot is based on the results of the meta-analysis in the first stage including AgP-GER, AgP-NL, CP-EA-sev and CP-EA-mod and excluding CP-Ger. a SNP rs729876 at 16p13.12, b SNP rs11084095 at 19p13.41, c SNP rs9982623 at 21q22.3, and d SNP rs9984417 at 21q22.1

Fig. 3

Regional association plots of the loci with P < 10⁻⁶ for the lead variants identified after removing the smallest sample of AgP-NL. Due to the low number of variants that were existent in all samples, this plot is based on the results of the meta-analysis in the first stage including AgP-GER, CP-EA-sev, and CP-EA-mod and excluding CP-Ger. a SNP rs16870060 at 8q22.3 and b SNP rs2064712 at 6q26