Causal relationship between molecular markers of biological aging and orthopedic diseases: A two-sample bidirectional Mendelian randomization study

Abstract

Background: Studies indicate an association between biological aging and orthopedic diseases, but the causality remains unclear. Aims: This study aims to investigate the bidirectional causal relationship between molecular markers of biological aging age and orthopedic conditions. Methods: A two-sample Mendelian randomization (MR) analysis based on a genome-wide association study (GWAS) was conducted to explore these causal relationships. Analysis methods included inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. Sensitivity analyses involved Cochran's Q, MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Results: The forward MR analysis identified several causal relationships: granulocyte proportions influenced intervertebral disc degeneration (IVDD) (OR 0.2316, P = 0.0101) and low back pain (LBP) (OR 0.2624, P = 0.007); telomere length (TL) affected cervical spondylosis (C/S) (OR 0.8759, P = 0.0167) and IVDD (OR 0.9184, P = 0.023); fibroblast growth factor-23 (FGF-23) impacted frozen shoulder (FS) (OR 1.2424, P = 0.0316); and HannumAge influenced C/S (OR 0.9518, P = 0.0233). The reverse MR analysis found that FS influenced TL (OR 0.9582, P = 0.0002) and α-Klotho (OR 0.7592, P = 0.0256), while sciatica affected TL (OR 0.9344, P = 0.0055) and C/S impacted PhenoAge (OR 1.6583, P = 0.0131) after outlier exclusion. Cochran's Q indicated heterogeneity in certain analyses, and MR-Egger showed no horizontal pleiotropy in significant causal associations. Conclusions: This study suggests a potential causal associations between molecular markers of biological aging and orthopedic diseases, suggesting avenues for future research into the underlying mechanisms.

Keywords

• Epigenetic age
• Orthopedic diseases
• Mendelian randomization
• Causal relationship
• GAWS
• Aging