A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci.

AIM: Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at ≤35 years of age was performed. MATERIALS AND METHODS: Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age ≤35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data. RESULTS: The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 × 10-9 ), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p < 10-5 , including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 × 10-8 ). CONCLUSIONS: This study expands the set of known genetic loci for severe periodontitis with an age of onset ≤35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health.

Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study.

Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the "Axiom Spanish Biobank" array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10-5, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10-5, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10-5, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10-5, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10-5, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10-2, p = 5.1 × 10-3, p = 1.2 × 10-2, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response.

Genome-wide association study of stage III/IV grade C periodontitis (former aggressive periodontitis) in a Spanish population.

AIM: To identify loci associated with stages III/IV, grade C periodontitis (PIII/IV-C) through a genome-wide association study (GWAS). MATERIALS AND METHODS: 441 Caucasian Spanish PIII/IV-C cases from the SEPA Network of Research Clinics and 1141 controls from the Banco Nacional de ADN were genotyped with "Axiom Spain Biobank Array," which contains 757836 markers, including rare and low-frequency Spanish variants. The analysis of the individual association and subsequently the gene-level analysis with Sequence Kernel Association Test (SKAT) were carried out adjusting for age, sex and PC1 covariates. Pathway Analysis was additionally performed with Ingenuity Pathway Analysis (IPA) software on the top associated genes. RESULTS: In the individual analyses, no genome-wide significant signals were detected. However, 8 SNPs of 8 loci reached suggestive evidence of association with PIII/IV-C, including FAT3 rs35709256, CSNK1G2 rs4807188, MYH13 rs2074872, CNTN2 rs116611488, ANTXR1 rs4854545, 8p23.2 rs78672540, ANGPT1 rs13439823 and PLEC rs11993287 (p < 5 × 10-6 ). SKAT analysis identified other interesting signals at CNTN2, FBXO44, AP1M2, RSPO4, KRI1, BPIFB1 and INMT, although their probability does not exceed the multiple-test correction. IPA indicated significant enrichment of pathways related to cAMP, IL-2, CD28, VDR/RXR and PI3K/Akt.  CONCLUSIONS: GWAS found no SNPs significantly associated with PIII/IV-C.

Assessment of genotyping tools applied in genetic susceptibility studies of periodontal disease: A systematic review.

OBJECTIVE: A systematic review to evaluate the various genotyping tools and study strategies employed to define genetic susceptibility to periodontitis. METHODS: The review was performed in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The search for publications referring to the genetic bases of periodontal disease was performed on the MEDLINE-PubMed and Cochrane Library databases, on trials registers, and on the web pages of regulatory agencies. RESULTS: We found 2439 potentially eligible articles, of which only 25 satisfied the established inclusion criteria and were processed for data extraction. The review revealed marked heterogeneity between studies, caused in part by the lack of a universally accepted definition for periodontitis phenotypes and by the variety of genotyping tools available. The most commonly used technique was genotyping candidate genes. CONCLUSION: The few rigorous studies that have been published on genetic susceptibility to periodontitis are subject to severe methodological bias due to their design and the genotyping tools employed. Despite their limitations, candidate gene studies continue to be the predominant methodological approach, rather than genome-wide association studies. Further studies must be designed using a universally accepted, validated diagnostic criterion for periodontitis, analysing multiple genes and polymorphisms in combination with rare variants.

The scale-of-choice effect and how estimates of assortative mating in the wild can be biased due to heterogeneous samples.

The mode in which sexual organisms choose mates is a key evolutionary process, as it can have a profound impact on fitness and speciation. One way to study mate choice in the wild is by measuring trait correlation between mates. Positive assortative mating is inferred when individuals of a mating pair display traits that are more similar than those expected under random mating while negative assortative mating is the opposite. A recent review of 1134 trait correlations found that positive estimates of assortative mating were more frequent and larger in magnitude than negative estimates. Here, we describe the scale-of-choice effect (SCE), which occurs when mate choice exists at a smaller scale than that of the investigator's sampling, while simultaneously the trait is heterogeneously distributed at the true scale-of-choice. We demonstrate the SCE by Monte Carlo simulations and estimate it in two organisms showing positive (Littorina saxatilis) and negative (L. fabalis) assortative mating. Our results show that both positive and negative estimates are biased by the SCE by different magnitudes, typically toward positive values. Therefore, the low frequency of negative assortative mating observed in the literature may be due to the SCE's impact on correlation estimates, which demands new experimental evaluation.