As one of the most common chronic disorders, obesity has raised alarming interest worldwide due to its significant impact on social cost and life expectancy (1). Obesity is associated with multiple musculoskeletal disorders including osteoarthritis, intervertebral disc disease (IVDD), sciatica, and low back pain (LBP) and thus reduced the motility and life quality of the patients (1–3).

IVDD is a common degenerative disorder characterized by the progressive loss of proteoglycans and water content in the nucleus pulposus (NP) and may eventually result in the breakdown of the discs in between the vertebras (4, 5). Degenerated discs are more prone to be out-pouching (herniation) and may press against spinal nerves and the nerve root. Although asymptomatic in various cases, disc degeneration is known to be associated with disc herniation or prolapse, low back pain, and sciatica (6–8). When nerves are irritated in the lower back due to IVDD, this condition is referred to as lumbar radiculopathy. When this happens to the L4-S1 nerve roots, it leads to a commonly recognized pain called sciatica (8, 9).

The etiology and pathophysiology of IVDD are still not fully characterized yet. It may be the result of a combination of genetic background and environmental factors including aging, overloading, physical activity, and smoking (10–12). Endplate defect has been shown to be the major initiating factor contributing to IVDD and Modic changes (13–17). Previous studies also noticed an association between obesity and increased IVDD risk (18–20). Rade et al. suggested that high BMI may increase the risk of IVDD through predisposing the endplate defect (16). However, these studies are mostly cohort or cross-sectional studies and are unable to conclude a causal relationship. Furthermore, there are studies that provided conflicting evidence against the association (21).

Mendelian randomization (MR) is a method that uses single-nucleotide polymorphism (SNP) as instrumental variables for estimating the causal effect of an exposure on an outcome (22, 23). Since genetic variants are randomly assigned, the study is protected from potential confounding factors (24). Besides, since the SNP alleles are assigned during the meiosis before the onset of the disease, the risk of reverse causality is minimized. The aim of the study is to assess the causal associations between body mass index (BMI)/obesity-related traits and dorsopathies including IVDD, LBP, and sciatica with a two-sample MR approach.

In the current study, we investigated the causal relationships between BMI/obesity-related traits and different dorsopathies by using multiple MR methods. This study indicated that a higher BMI was an important risk factor causally associated with the various dorsopathies.

Previous studies agreed on whether elevated BMI, especially being overweight or obese, promotes the development of IVDD. Özcan-Ekşi et al. have shown that the severity of IVDD at L4-L5 and L5-S1 disc levels was closely associated with BMI in women with LBP. The women with severe IVDD at L4-L5 and L5-S1 disc levels were more overweight or obese when compared to those with mild-to-moderate IVDD, respectively (30415054) Recently, Özcan-Ekşi et al. evaluated 151 patients with LBP in terms of IVDD, end-plate changes, and fatty infiltration in the paraspinal muscles at all lumbar levels. They found that obese patients had more severe IVDD than non-obese patients at L4-L5. They suggested that the difference might be due to unbalanced shear forces at lower lumbar levels, particularly in women (37). A cohort study conducted by Liuke et al. found that the persistence of overweight (BMI ≥ 25 kg/m²) is strongly associated with the number of lumbar discs with decreased intensity of nucleus pulposus under magnetic resonance imaging (MRI) (18). Furthermore, they also noticed that overweight at a young age was positively correlated with the number of degenerated lumbar discs at middle age. These findings are consistent with our observations by using the MR method since the MR estimates the effects of a given exposure over a lifelong time (38).

A cross-sectional study conducted by Samartzis et al. has also shown that subjects in the group of disc degeneration have significantly higher BMI values (mean 23.3 kg/m²) compared to subjects without degeneration (mean 21.7 kg/m²) (19). Also, they showed that in the group with elevated BMI, there is a significant increase in the number of degenerated discs and the severity of degeneration. Similarly, a meta-analysis enrolling 1,749 patients with lumbar disc diseases and 1,885 controls suggested that overweight increased the risk of lumbar disease and is a predominant factor compared with age and sex with a subgroup analysis (39). Accumulating evidence has shown that endplate defect is an initiating factor that triggers IVDD (13–17). BMI has been suggested to contribute to IVDD through endplate defect (16).

On the contrary, several other studies provided evidence against such an association. Videman et al. performed an exposure-discordant twin study and reported that elevated BMI increased the bone mineral density of lumbar vertebrae, lumbar disc height, and intensity (21). A recent observational study enrolling 1,128 female twins found that BMI was weakly associated with chronic back pain in results from analyzing the total samples; however, the association disappeared after adjusting for the shared environment and genetic factors by using within-pair case–control analysis (40). Interestingly, they also assessed the effect of waist circumference and waist–hip ratio on chronic low back pain and noticed that higher waist-hip ratios appeared to be a protective factor for low back pain with an OR of 0.67 (95% CI 0.47–0.94) while no effect was found for waist circumference. The different observations may be due to the study design of the previous publications, which are mostly observational and cannot rule out the effect of confounders or reverse causality.

Several biomechanical studies quantified the mechanical forces exerted on low back and intervertebral disc. Singh et al. demonstrated that in severely obese patients (BMI ≥ 35 kg/m2), the L5/S1 disc compression forces exceeded the 3,400-N NIOSH action limit (range from 3,000 to 8,500 N) (41). Meanwhile, the group mean disc compression force is significantly higher in severely obese patients as compared with the normal-weight group (41). Coppock et al. developed non-invasive magnetic resonance imaging and solid modeling techniques to measure the in vivo intervertebral disc (IVD) deformation following treadmill walking stress test, and the study showed the highest statistical significant association between BMI and compressive deformation in the L5-S1 IVD (R2 = 0.61, p < 0.05), and the association became weaker in the L3-L4 and L4-L5 IVDs (42). Another study showed that as body weight increased from 51 to 119 kg, the L5-S1 compression increased by ~80%–147% with no load in hands and by ~46%–52% in load holding tasks in flexed postures. In addition, spinal loads further increased by up to 15% in severely obese individuals (BMI > 30 kg/m2) (43). In summary, obese patients are at a higher risk of IVDD-associated outcomes due to higher mechanical forces exerted on lumbar IVD in both normal and mechanical loading conditions.

In this current study, we assessed the causal effect of waist circumference, hip circumference, and waist–hip ratio on IVDD, sciatica, and LBP with MR methods. A significant effect on IVDD was observed with waist circumference and hip circumference, but not with waist–hip ratio. Similarly, higher waist and hip circumference increased the risk of sciatica with lumbago in our analysis. The causal effect of waist and hip circumference on IVDD disappeared after the adjustment for BMI with multivariable MR, while whole body fat-free mass remained consistent. This might be due to the high correlation between body fat-free mass/muscle mass and heavy physical labor which is another risk factor for IVDD.

Damaged lumbar intervertebral disc and endplates can lead to compression on nerve roots, resulting in traumatic neuropathic pain (9). Shiri et al. found that overweight and obesity were positively correlated with the risk of hospitalization for sciatica and lumbar radicular pain in a meta-analysis of 26 studies (44). Similarly, a recent meta-analysis of 10 cohort studies including 29,748 subjects has indicated that overweight and obesity are risk factors for the development of LBP in both genders (45). These findings are consistent with our results from MR analyses that genetically proxied BMI is positively correlated with the risk of sciatica and LBP. Even though other body composition factors also showed causal relationships with sciatica and LBP, these relationships disappeared after adjusting for the effect of BMI ( Figures 2 – 4 ).

Since BMI is highly related to sedentary behaviors, we have also performed a mediation analysis to estimate the proportion of BMI’s effect mediated by leisure sedentary behavior (television watching). We showed that 41.4% (95% CI, 21.8%, 64.8%), 33.8% (95% CI, 17.5%, 53.4%), and 49.7% (95% CI, 29.4%, 73.5%) of BMI’s effect on IVDD, sciatica, and LBP were indirect effects mediated by sedentary behavior. These results suggested that BMI posed a deleterious effect on IVDD, sciatica, and LBP independent of leisure sedentary behavior.

The first advantage of using the MR method is that we could study the effect of BMI on IVDD, sciatica, and LBP by using publicly available large GWAS datasets. Since genetic variant alleles are assigned randomly, the causal estimates are less prone to confounding factors and reverse causality. Furthermore, bias because of population stratification could be mitigated by confining the study population to European ancestry.

However, there are several limitations to this study. Firstly, distortion of estimates from MR analyses may happen due to the existence of pleiotropy, which is when one genetic instrument is associated with more phenotypes other than the exposure of interest. We have used MR-Egger as sensitivity analysis for detecting potential pleiotropy, and no significant pleiotropy was identified.

In conclusion, our comprehensive MR study provides evidence that higher BMI is causally associated with the risk of IVDD, sciatica, and LBP. Weight control should be considered in populations with obesity to reduce the risk of dorsopathies including IVDD, sciatica, and LBP.

Publicly available datasets were analyzed in this study. These data can be found here as follows: the sources of GWAS data included in the study are presented in the article/ Supplementary Tables 1 , 2 . Further inquiries can be directed to the corresponding authors.

Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

ZL and HH conceptualized and designed the study. ZL, JZ, JM, and YP performed data analysis. ZL, JZ, and JM wrote the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by the Nature Science Foundation of Shandong Province (No. ZR2016HL11) and Undergraduate Training Program for Innovation and Entrepreneurship of Shandong Province (S202010438060).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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