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

Maria K Sobczyk; Benjamin G Faber; Lorraine Southam; Monika Frysz; April Hartley; Eleftheria Zeggini; Genetics of Osteoarthritis Consortium; Haotian Tang; Tom R Gaunt

doi:10.1016/j.joca.2023.12.003

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

Osteoarthritis Cartilage. 2023 Dec 30:S1063-4584(23)01017-8. doi: 10.1016/j.joca.2023.12.003. Online ahead of print.

Authors

Maria K Sobczyk¹, Benjamin G Faber², Lorraine Southam³, Monika Frysz⁴, April Hartley⁵, Eleftheria Zeggini⁶; Genetics of Osteoarthritis Consortium; Haotian Tang⁷, Tom R Gaunt⁸

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. Electronic address: maria.sobczyk@bristol.ac.uk.
² MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom; Musculoskeletal Research Unit, University of Bristol, Bristol, UK. Electronic address: ben.faber@bristol.ac.uk.
³ Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany. Electronic address: lorraine.southam@helmholtz-muenchen.de.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom; Musculoskeletal Research Unit, University of Bristol, Bristol, UK. Electronic address: monika.frysz@bristol.ac.uk.
⁵ MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. Electronic address: april.hartley@bristol.ac.uk.
⁶ Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, 81675 Munich, Germany. Electronic address: eleftheria.zeggini@helmholtz-muenchen.de.
⁷ MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. Electronic address: haotian.tang@bristol.ac.uk.
⁸ MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. Electronic address: tom.gaunt@bristol.ac.uk.

PMID: 38160745
DOI: 10.1016/j.joca.2023.12.003

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.