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Genetic and epidemiological evidence linking respiratory and musculoskeletal diseases: shared risk factors and
Olivia Murrin1, Bethany Voller2, Ruby M Woodward3
1Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK. o.murrin@exeter.ac.uk.
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.
Insights
Musculoskeletal and respiratory diseases show causal links, with common risk factors like obesity and smoking. Interventions targeting physical function and cardiovascular health may prevent multimorbidity.
Area of Science:
- Genetics and Epidemiology
- Public Health
- Rheumatology and Pulmonology
Background:
- Genetic correlations identified between musculoskeletal (MSK) and respiratory conditions.
- Prevention strategies for MSK-respiratory multimorbidity are underexplored.
- This study investigates causal links and modifiable factors for MSK-respiratory disease pairs.
Purpose of the Study:
- Evaluate potential causal relationships between MSK and respiratory conditions.
- Identify modifiable risk factors contributing to disease progression.
- Quantify intervention windows for preventing multimorbidity.
Main Methods:
- Two-sample Mendelian randomization (MR) for causal inference.
- Analysis of linked electronic health records (CPRD, N=11,042,985, age ≥ 40).
- Assessment of disease trajectories, prognostic consequences, and mediation by modifiable factors.
Main Results:
- Bidirectional relationships found between COPD and RA/OA, and asthma and RA/OA.
- COPD liability increased PMR risk; psoriasis liability increased COPD and asthma risk.
- Obesity, smoking, hypertension, and thyroid conditions identified as common risk factors; intervention windows of 5-13 years.
Conclusions:
- MSK and respiratory conditions often develop sequentially over years.
- Targeted strategies promoting physical function and optimizing lipid/cardiovascular risk management are key.
- Interventions may delay or prevent multimorbidity progression.
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