Background: We previously identified genetic correlation between pairs of musculoskeletal (MSK) and respiratory conditions. Strategies to prevent or delay their onset remain underexplored in the context of multimorbidity. This study investigated whether MSK-respiratory disease pairs show evidence of potential causal relationships, identified modifiable risk factors, and quantified intervention windows to prevent progression to multimorbidity.

Methods: We examined combinations of one respiratory condition (asthma, COPD) and one MSK condition [rheumatoid arthritis (RA), osteoarthritis (OA), polymyalgia rheumatica (PMR), psoriasis]. Two-sample Mendelian randomisation (MR) evaluated potential causal relationships in both directions. Linked electronic health records from CPRD (N = 11,042,985; age ≥ 40 years) were used to assess longitudinal disease trajectories, prognostic consequences, and mediation by potentially modifiable or treatable factors.

Results: We found evidence for bidirectional relationships between COPD and RA/OA (ORs 1.10-1.19) and between asthma and RA/OA (ORs 1.03-1.14). COPD genetic liability also increased PMR risk (OR 1.14, 95% CI 1.03-1.25). Psoriasis liability increased risk of COPD (OR 1.04, 95% CI 1.02-1.07) and asthma (OR 1.05, 95% CI 1.03-1.08). Across disease pairs, the median interval between first and second diagnoses was 5-13 years, indicating a substantial window for intervention. Obesity, smoking, hypertension, and thyroid conditions were risk factors common across all studied conditions. Mediation analyses suggested reduced physical activity and lipid changes partially contributed to the onset of respiratory disease following MSK conditions. Colocalisation identified genetic variants causal for specific condition pairs (implicating genes IFIH1, APOE, and CXCR5), highlighting inflammatory and lipid pathways.

Conclusions: MSK and respiratory conditions commonly develop sequentially over many years. Targeted strategies promoting physical function, optimising lipid and cardiovascular risk management may help delay or prevent multimorbidity progression.