Investigating the shared genetic architecture of osteoarthritis and frailty: a genome-wide cross-trait analysis.

Observational studies suggest a link between osteoarthritis (OA) and frailty, but the shared genetic architecture and causal relationships remain unclear. We analyzed X-ray and ¹⁸F-FDG PET/CT images in frail and non-frail individuals and conducted genetic correlation analyses using Linkage Disequilibrium Score Regression (LDSC) based on recent Genome-Wide Association Studies (GWAS) for OA and frailty. We identified pleiotropic single-nucleotide polymorphisms (SNPs) through Cross-Phenotype Association (CPASSOC) and Colocalization (COLOC) analyses and investigated genetic overlaps using Multi-marker Analysis of GenoMic Annotation (MAGMA). Transcriptome-wide association studies (TWAS) were conducted to analyze pleiotropic gene expression, and Mendelian Randomization (MR) was used to assess causal relationships between OA and frailty. Frail individuals showed more severe OA on X-ray (67% vs. 31%, P ≤ 0.01) and higher SUVmax on ¹⁸F-FDG PET/CT (4.1 vs. 3.6, P < 0.05) compared to non-frail individuals. Genetic correlation between frailty and OA was significant (rg = 0.532, P = 4.230E-88). Cross-trait analyses identified 42 genomic loci and 138 genes shared between the conditions. COLOC analysis revealed 2 pleiotropic loci, while TWAS identified 27 significant shared genetic expressions in whole blood and musculoskeletal tissue. Bidirectional MR indicated that OA increases the risk of frailty (IVW: beta: 0.13, P = 1.52E-08) and vice versa (IVW: beta: 0.73, P = 1.66E-04). Frail individuals exhibit more severe imaging features of OA. The shared genetic basis between OA and frailty suggests an intrinsic link, providing new insights into the relationship between these conditions.