Abstract
Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, but phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorder that shares common features with LDD, also showed genetic correlations with height, BMI and BMD. The findings suggest a common key contribution of biomechanical stress to the pathogenesis of LDD and will direct the future search for pleiotropic genes.
Highlights
Human intervertebral discs (IVDs) are fibrocartilaginous structures that lie between adjacent vertebrae
We focused on two major aspects of Lumbar disc degeneration (LDD) captured by different magnetic resonance imaging (MRI) features (Figure 2a)
We adopted a trans-ethnic PGS strategy to evaluate the genetic overlaps between different traits where GWAS of base phenotypes were done in Europeans and validation and testing samples were East Asians
Summary
Human intervertebral discs (IVDs) are fibrocartilaginous structures that lie between adjacent vertebrae. These IVDs hold the vertebrae together, facilitate some vertebral motion, and act as shock absorbers to accommodate biomechanical loads (Oxland, 2016). Magnetic resonance imaging (MRI) is the gold-standard for evaluating disc degeneration. Based on this imaging, numerous methods are available to grade and summarize different features indicative of degeneration, including signal intensity loss, bulging and herniation, as well as disc space narrowing (Battié et al, 2004; Cheung et al, 2009). Its severe form lumbar disc herniation (LDH), in which disc material herniates into the epidural space and compresses a lumbar nerve root, can cause neuropathic pains (sciatica) radiating to the lower extremity (Ropper and Zafonte, 2015)
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