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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., (© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Variants in the long noncoding RNA (lncRNA) gene CDKN2B-AS1 (CDKN2B antisense RNA 1; ANRIL) are genome-wide associated with type 2 diabetes (T2D), atherosclerosis, and several forms of cancer. However, it is currently not understood how CDKN2B-AS1 transcripts translate into diabetes. We previously demonstrated trans-regulation of the proximal polyadenylated transcripts on several genes with functions in glucose and lipid metabolism. However, information on specific genes that are regulated at physiological concentrations by the distal polyadenylated CDKN2B-AS1 transcripts is lacking. To identify target genes of CDKN2B-AS1 trans-regulation, we designed inducible short hairpin RNA constructs and integrated them into the genome of T-Rex HEK293 cells. Changes of gene expression after induction were determined at defined time points by genome-wide mRNA expression analysis. We confirmed downregulation of RBMS1, located on chromosome 2 (RNA-binding motif, single-stranded interacting protein 1) at the transcript and protein level in stable-transfected, inducible HeLa cells, and demonstrated that the effect was independent of the cell type, known cis-regulatory effects, and regulation of the proximal polyadenylated CDKN2B-AS1 isoforms. Direct binding of CDKN2B-AS1 transcripts to RBMS1 was shown by RNA immunoprecipitation. RBMS1 encodes a cell cycle suppressor. We conclude that the distal and proximal polyadenylated CDKN2B-AS1 transcripts have separate functions in gene regulation, which are independent of the circular CDKN2B-AS1 isoforms and of the genes CDKN2A/2B.

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.

Oral health and disease are known to be influenced by complex interactions between environmental (e.g., social and behavioral) factors and innate susceptibility. Although the exact contribution of genomics and other layers of "omics" to oral health is an area of active research, it is well established that the susceptibility to dental caries, periodontal disease, and other oral and craniofacial traits is substantially influenced by the human genome. A comprehensive understanding of these genomic factors is necessary for the realization of precision medicine in the oral health domain. To aid in this direction, the advent and increasing affordability of high-throughput genotyping has enabled the simultaneous interrogation of millions of genetic polymorphisms for association with oral and craniofacial traits. Specifically, genome-wide association studies (GWAS) of dental caries and periodontal disease have provided initial insights into novel loci and biological processes plausibly implicated in these two common, complex, biofilm-mediated diseases. This paper presents a summary of protocols, methods, tools, and pipelines for the conduct of GWAS of dental caries, periodontal disease, and related traits. The protocol begins with the consideration of different traits for both diseases and outlines procedures for genotyping, quality control, adjustment for population stratification, heritability and association analyses, annotation, reporting, and interpretation. Methods and tools available for GWAS are being constantly updated and improved; with this in mind, the presented approaches have been successfully applied in numerous GWAS and meta-analyses among tens of thousands of individuals, including dental traits such as dental caries and periodontal disease. As such, they can serve as a guide or template for future genomic investigations of these and other traits.

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation., Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases., Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015., Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available., Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population., Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation., Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15])., Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.