Causal relationships between anthropometric traits, bone mineral density, osteoarthritis and spinal stenosis: A Mendelian randomisation investigation

Abstract

Objective: Spinal stenosis is a common condition among older individuals, with significant morbidity attached. Little is known about its risk factors but degenerative conditions, such as osteoarthritis (OA) have been identified for their mechanistic role. This study aims to explore causal relationships between anthropometric risk factors, OA, and spinal stenosis using Mendelian randomisation (MR) techniques.

Design: We applied two-sample MR to investigate the causal relationships between genetic liability for select risk factors and spinal stenosis. Next, we examined the genetic relationship between OA and spinal stenosis with linkage disequilibrium score regression and Causal Analysis Using Summary Effect estimates MR method. Finally, we used multivariable MR (MVMR) to explore whether OA and body mass index (BMI) mediate the causal pathways identified.

Results: Our analysis revealed strong evidence for the effect of higher BMI (odds ratio [OR] = 1.54, 95%CI: 1.41-1.69, p-value = 2.7 × 10^-21), waist (OR = 1.43, 95%CI: 1.15-1.79, p-value = 1.5 × 10^-3) and hip (OR = 1.50, 95%CI: 1.27-1.78, p-value = 3.3 × 10^-6) circumference on spinal stenosis. Strong evidence of causality was also observed for higher bone mineral density (BMD): total body (OR = 1.21, 95%CI: 1.12-1.29, p-value = 1.6 × 10^-7), femoral neck (OR = 1.35, 95%CI: 1.09-1.37, p-value = 7.5×10^-7), and lumbar spine (OR = 1.38, 95%CI: 1.25-1.52, p-value = 4.4 × 10^-11). We detected high genetic correlations between spinal stenosis and OA (rg range: 0.47-0.66), with Causal Analysis Using Summary Effect estimates results supporting a causal effect of OA on spinal stenosis (OR_allOA = 1.6, 95%CI: 1.41-1.79). Direct effects of BMI, BMD on spinal stenosis remained after adjusting for OA in the MVMR.

Conclusions: Genetic susceptibility to anthropometric risk factors, particularly higher BMI and BMD can increase the risk of spinal stenosis, independent of OA status. These results may inform preventative strategies and treatments.

Keywords: Body mass index; Bone mineral density; Lumbar stenosis; Mendelian randomisation; Osteoarthritis; Spinal stenosis.

Fig. 1

Flowchart providing overview of datasets and methods used in the current MR study.

Fig. 2

Two sample Mendelian randomisation results for the effect of genetic susceptibility for adiposity traits (A – BMI, B – hip circumference, C - waist circumference, D – waist-to-hip ratio) on spinal stenosis (FinnGen and UK BioBank). Plots compare results obtained using IVW and outlier-robust MR-PRESSO method and display fixed-effects meta-analysis results of the odds ratio per SD increase in exposure obtained using FinnGen and UK Biobank outcomes.

Fig. 3

Two sample Mendelian randomisation results for the effect of genetic susceptibility for skeletal traits (A – height, B – total body BMD, C – femoral neck BMD, D – lumbar spine BMD) on spinal stenosis (FinnGen and UK Biobank). Plots compare results obtained using IVW and outlier-robust MR-PRESSO method and display fixed-effects meta-analysis results of the odds ratio per SD increase in exposure obtained using FinnGen and UK Biobank outcomes.

Fig. 4

Genetic correlation of osteoarthritis and spinal stenosis phenotypes estimated by LD score regression. Correlation coefficients are displayed within cells and the colour/area of the cells are proportionally scaled. All p-values are significant after FDR correction. FDR, false discovery rate, FINN_SS, FinnGen spinal stenosis, UKBB_SS, UK Biobank spinal stenosis.

Fig. 5

Multivariable Mendelian randomisation results for the jointly modelled effect of genetic susceptibility for risk factors (A – BMI, B – height, C – total body BMD, D – femoral neck BMD) and liability for osteoarthritis (all or spine) on spinal stenosis (FinnGen). The odds ratios are scaled per SD increase of risk factors and doubling in the odds of osteoarthritis.

Fig. 6

Summary diagrams illustrating direct and indirect, osteoarthritis (all sites)-mediated effects of risk factors (A – BMI, B – height, C – total body BMD, D – femoral neck BMD) on spinal stenosis (FinnGen). OR indicates odds ratio (with 95% CI).