PHEWAS, TWAS, Mendelian Randomization in Osteoporosis Research: the good, the bad, and the ugly.

PURPOSE OF REVIEW: While GWAS has identified many loci associated with bone mineral density (BMD), translating these findings into functional insights and treatments remains challenging. Post-GWAS methods such as Transcriptome-Wide Association Study (TWAS), Phenome-Wide Association Study (PheWAS), and Mendelian Randomization (MR) provide complementary strategies to prioritize genes and causal risk factors. This review summarizes findings from these studies. RECENT FINDINGS: TWASs have identified many potential causal genes for BMD, but only a few, such as PPP6R3, have been confirmed through functional validation. Several MR studies have provided increasing evidence of causal relationships between inflammatory bowel disease, NAFLD, COPD, and lower BMD, along with a higher risk of osteoporosis. PheWAS and MR also identify bone marrow fat as a risk factor for decreased BMD. It is essential to bridge the critical gap between statistical discovery and biological validation. Moreover, the lack of bone-specific transcriptomic data remains a significant limitation, underscoring the need to generate such datasets. At the same time, all MR evidence should be corroborated with other sources to strengthen causal conclusions.