Investigating The Bidirectional Relationship Between Low Back Pain, Hip Pain, Knee Pain, And Gait Abnormalities: A Mendelian Randomization Study

Summary

IVW analyses suggest low back and hip pain may be associated with gait abnormalities, whereas knee pain and reverse associations remain inconclusive.

Abstract

Gait abnormalities are associated with altered lower-limb biomechanics and functional impairment in musculoskeletal disorders. Although low back pain, hip pain, and knee pain have been linked to impaired gait in observational studies, their causal relationships remain unclear. We conducted a bidirectional Mendelian randomization (MR) study to assess potential causal associations between site-specific pain and gait abnormalities. Independent single nucleotide polymorphisms from large-scale genome-wide association studies were used as genetic instruments for low back pain, hip pain, and knee pain. Gait abnormalities, defined in the source GWAS as self-reported difficulty walking, were used as the outcome in forward MR analyses and as the exposure in reverse MR analyses. The inverse-variance weighted (IVW) method was the primary analysis, supported by sensitivity analyses for heterogeneity, horizontal pleiotropy, and robustness. In forward analyses, genetically predicted low back pain (OR = 1.53, 95% CI = 1.058–2.219, P = 0.024) and hip pain (OR = 1.55, 95% CI = 1.067–2.252, P = 0.021) were associated with increased risk of gait abnormalities in IVW analyses. However, the four additional MR methods were not statistically significant, although estimates were generally directionally consistent. Genetically predicted knee pain showed no significant association (OR = 2.15, 95% CI = 0.234–19.789, P = 0.498), with substantial uncertainty reflected by the wide confidence interval. Reverse MR analyses found no evidence that genetic liability to gait abnormalities increased the risk of low back, hip, or knee pain, although only four gait-abnormality SNPs were available. No substantial heterogeneity or horizontal pleiotropy was detected. Overall, this study provides limited IVW-based genetic evidence that low back pain and hip pain may be associated with gait abnormalities. Findings should be interpreted cautiously and validated using larger GWAS datasets with refined phenotypes.

Introduction

Gait abnormalities can stem from motor or sensory impairments, and their clinical features are contingent upon the location and nature of the underlying pathology. Specific abnormal gait patterns may provide important diagnostic clues for particular diseases. Notably, in musculoskeletal disorders, gait abnormalities often present with distinctive biomechanical characteristics and are closely related to pain, joint dysfunction, and reduced mobility^1,2,3. Studies have shown that long-term gait abnormalities can aggravate the condition of patients with osteoarthritis

Protocol

This study used publicly available genome-wide association study (GWAS) summary-level data from the IEU OpenGWAS database and GWAS Catalog. No individual-level participant data were accessed, and no new human participants were recruited. Ethical approval and written informed consent had been obtained in the original contributing GWAS studies. Therefore, additional institutional review board approval was not required for the present secondary analysis of publicly available summary statistics.

Study principle and design

The basic steps of MR study include obtaining GWAS summary data, screening and ....

Results

GWAS data for three site-specific musculoskeletal pain phenotypes, including low back pain, hip pain, and knee pain, and one gait-abnormality phenotype were analyzed in this study. Detailed information on IVs for each exposure factor can be found in Supplementary File 3.

MR analysis of site-specific musculoskeletal pain on gait abnormalities

In this study, SNPs with linkage disequilibrium and palindromic structure were excluded and .......

Discussion

Gait abnormalities can alter lower-limb joint loading and movement strategies, potentially accelerate 821+_osteoarthritic processes and contributing to functional limitations that markedly impair quality of life. This clinical relevance has drawn increasing attention to the interplay between gait dysfunction and musculoskeletal pain. Observational studies suggest that site-specific musculoskeletal pain may be associated with impaired gait; for example, a cross-sectional study of community-dwelling older adults aged 65 ye.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
IEU OpenGWAS database	MRC Integrative Epidemiology Unit, University of Bristol	N/A	Source of GWAS summary statistics for exposure and outcome phenotypes.
MR-PRESSO R package	Marie Verbanck / R package	N/A	Used for outlier detection and assessment of horizontal pleiotropy.
PhenoScanner V2	University of Cambridge	V2	Web resource used to identify SNPs associated with potential confounders.
R	R Foundation for Statistical Computing	Version 4.3.2	Statistical computing environment used for MR analysis and quality control.
TwoSampleMR R package	MRC Integrative Epidemiology Unit, University of Bristol	Version 0.5.8	Used for IVW, MR-Egger, weighted median, weighted mode, and simple mode MR analyses.