Abstract: BACKGROUND: It has been found in recent observational studies that assessing localized fat mass is crucial in the evaluation of disc degeneration. Although obesity has been recognized as a risk factor for disc degeneration, the causal relationship between fat mass, which is a key factor in obesity, and intervertebral disc degeneration has been unclear in previous studies.
OBJECTIVE: To investigate the causal risk factors of intervertebral disc degeneration associated with different distributions of fat mass, thereby enhancing the understanding of the pathogenesis of intervertebral disc degeneration and contributing to the development of preventive, therapeutic, and prognostic strategies.
METHODS: Genetic markers associated with trunk and lower limb fat mass were extracted as instrumental variables from the publicly available IEU Open GWAS under the conditions of strong correlation and fulfillment of linkage disequilibrium. These markers were combined with the Mendelian randomization analysis to investigate the relationship between body fat and intervertebral disc degeneration. We used the latest version 9 database of FinnGen and assessed the results using several regression models, including inverse variance weighting, MR-Egger regression, simple mode, weighted mode, and weighted median estimator. We also assessed the heterogeneity of the genetic markers using Cochran’s Q test, and multiplicity was assessed using the MR-Egger intercept test. Additionally, we used the leave-one-out method to determine the sensitivity of individual genetic markers to the causal effect of the exposure and outcome. The results were presented as odds ratios (OR) and 95% confidence intervals (CI).
RESULTS AND CONCLUSION: The results from the inverse variance weighting method revealed that there was a positive causal relationship between trunk fat mass and the risk of developing intervertebral disc degeneration (OR=1.25, 95% CI: 1.15-1.35, P < 0.001). Additionally, there was an inverse causal relationship between bilateral lower limb fat mass and the risk of developing intervertebral disc degeneration (OR=0.7, 95% CI: 0.63-0.78, P < 0.001; OR=0.69, 95% CI: 0.62-0.76, P < 0.001). Furthermore, the MR-Egger intercept analysis did not detect any potential horizontal pleiotropy. No bias single nucleotide polymorphisms were detected, while heterogeneity tests were present, and the leave-one-out sensitivity analysis suggested reliable results. The results above demonstrate a positive causal relationship between trunk fat mass and intervertebral disc degeneration. As trunk fat mass increases, the risk of intervertebral disc degeneration rises. With an increase in both lower limb fat mass, the risk of intervertebral disc degeneration decreases. Fat content and distribution affects the risk of developing intervertebral disc degeneration and should be given more attention.

Key words: genome-wide association study, Mendelian randomization, intervertebral disc degeneration, fat mass, inverse variance weighting method, sensitivity analysis, single nucleotide polymorphism, causality