Identifying a genetic association between non-autoimmune diabetes & bone mass

Abstract

Introduction & Aim: Diabetes and osteoporosis are two common complex diseases that have a strong genetic and environmental component. The genetics of these diseases have been widely studied separately but not as extensively together. This project aims to elucidate the genetics underlying non-autoimmune diabetes and bone mineral density (BMD) through two study approaches; whole exome sequencing (WES) in cases with suspected monogenic diabetes participants and genotyping of two large collections of five literature derived variants. Methods: Five variants derived from the literature associated with both diabetes and BMD were selected for replication in two Maltese case-control studies (MOFS, n = 1174 and T2D, n = 773 collections). Ten non-obese probands with atypical non-autoimmune diabetes diagnosed before the age of 40 years were recruited. Lifestyle, biochemical data and BMD measurements were obtained and WES was carried out to identify possibly deleterious variants. Results: Significant associations between the five genotyped variants and bone and T2D phenotypes were observed, the most notable being within TNFRSF11B rs4876868, whereby the alternative allele was both deleterious for BMD at the TH and LS, and protective for T2D. The alternative allele of variant ADCY5 rs56371916 also appeared to increase fracture risk whilst increasing BMD at the LS and TH, indicating a possible alteration of bone microarchitecture. A polygenic risk score indicated that the five genotyped variants had a negative correlation with HOMA-IR in individuals without T2D and a positive correlation with BMI and HDL-c in T2D individuals. WES of ten probands identified a total of sixteen SNVs and InDels with a possible association with BMD, T2D or both. A missense variant in the GCK gene (c.1364T>A), was identified in one participant with accompanying osteoporosis at the LS, hinting at a potential detrimental effect on bone mass. Two participants also carried a rare frameshift variant in the WRAP53 gene (c.18_19delTC), indicating a likely association with T2D. Conclusion: A genetic link between BMD and T2D was established in literature derived variants and sixteen potentially pathogenic variants are identified through WES. Further confirmatory and functional studies for the shortlisted variants identified through WES are necessary in order to fully elucidate their effect on these two complex diseases.