Genetic Determinants of Bone Microarchitecture and its Association with Health Outcomes: A Genome-wide Association and Mendelian Randomization Study on Trabecular Bone Score

BackgroundBone microarchitecture is a critical determinant of bone strength and fracture risk, yet its genetic basis and relationship to systemic health remain largely unexplored. This study aimed to identify genetic determinants of bone microarchitecture using trabecular bone score (TBS) and investigate the causal relationships between bone microarchitecture and various health outcomes. MethodsWe conducted a genome-wide association study (GWAS) of TBS in 25,268 UK Biobank participants to identify genetic loci associated with bone microarchitecture. Two-sample Mendelian randomization (MR) was employed to assess the causal relationships between systemic health risk factors and bone microarchitecture, as well as the impact of bone microarchitecture on musculoskeletal disorders. FindingsThe GWAS identified 75 significant single nucleotide polymorphisms (SNPs) across 19 genomic loci, with an estimated heritability of TBS at 24.5%. Many of these loci (18/19) were also associated with bone mineral density (BMD) and fractures, indicating a shared genetic basis for bone microarchitecture and bone mass. MR analysis revealed that rheumatoid arthritis has a significant causal effect on the deterioration of bone microarchitecture ({beta} = -0.003, P = 1.14x10-4). Suggestive associations were found between bone microarchitecture deterioration and inflammatory bowel disease, cardiovascular disease, and depression (P < 0.05). Moreover, genetically predicted TBS was significantly associated with fracture risk (OR = 0.003, P = 1.89x10-8) and suggestively associated with osteonecrosis (OR = 0.002, P = 0.040). InterpretationThis study identified novel genetic determinants of bone microarchitecture and demonstrated its association with various systemic diseases, highlighting the critical role of bone microarchitecture in skeletal health. The results advocate for the clinical use of TBS to better assess the risk of osteoporosis and fractures and to improve bone and overall health assessments. The causal effect of rheumatoid arthritis on microarchitectural deterioration underscores the need for increased monitoring of bone health in this population. FundingThis work supported by Shanghai "Rising Stars of Medical Talent" Youth Development Program, Youth Medical Talents-Specialist Program (grant number SHHWRS 2023-62), the Fundamental Research Funds for the Central Universities (grant number AF0820060), Outstanding Research-oriented Doctor Cultivation Program at the Ninth Peoples Hospital affiliated with the School of Medicine, Shanghai Jiao Tong University, National Natural Science Foundation of China (grant number 31900941).