Causal relationship between trunk and lower limb fat mass and intervertebral disc disorders: A 2-sample Mendelian randomization study.

Intervertebral disc disorders (IVDDs) are a major cause of disability worldwide, influenced by genetic and lifestyle factors such as obesity. Although the role of body fat distribution in IVDDs is recognized, the causal relationship remains unclear. This study aimed to elucidate the genetic basis of this relationship by examining the association between fat mass distribution in the trunk and lower limbs and the risk of IVDDs using Mendelian randomization (MR). The study utilized single nucleotide polymorphism (SNP) as instrumental variable to investigate genetic predispositions to increased fat mass in specific body regions and their associations with IVDDs. Initially, 98,51,866 SNPs for trunk and lower limb fat mass and 21,304,570 SNPs for IVDDs were analyzed. Data cleaning steps, including linkage disequilibrium clumping, SNP merging, allele harmonization, and checks against the genome-wide association studies catalog database, reduced the number of relevant SNPs to 353 for trunk fat mass, and 346 and 337 for left and right leg fat mass, respectively. The causal analysis was conducted using the inverse variance weighted (IVW) method and MR-Egger method, with sensitivity analyses to test robustness. The IVW method showed a significant positive causal relationship between trunk fat mass and IVDDs (odds ratio (OR) = 1.274, 95% confidence interval (CI): 1.186-1.368, P < .001), whereas the MR-Egger method did not show statistical significance (P = .207). Both methods revealed a consistent and significant association for lower limb fat mass with IVDDs. Specifically, the IVW method indicated odds ratios of 1.454 (95% CI: 1.323-1.597, P < .001) for left leg fat mass and 1.467 (95% CI: 1.332-1.616, P < .001) for right leg fat mass. The presence of heterogeneity and potential pleiotropy was assessed, supporting the stability and reliability of the causal inferences. This study confirmed a positive causal relationship between trunk and lower limb fat mass and the risk of IVDDs, emphasizing the need to consider body fat distribution in IVDD prevention and management. The findings suggested that reducing trunk and lower limb fat mass could lower IVDD risk. This research provided valuable insights into the genetic and physiological links between body fat distribution and IVDDs, paving the way for targeted preventive strategies and therapeutic interventions.