Genes Leading to Intervertebral Disc Degeneration
Authors: Williams Frances M. K. 
Published: May 2014

Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem worldwide. LDD is characterized by several histological changes in and around the disc, including narrowing and dehydration of the disc, osteophyte growth at the adjacent vertebral body and end plate change. LDD has been shown in many studies to have a heritable basis. Several plausible candidate genes have been explored, and some associations have been replicated.1 More recently, genome-wide association (GWA) studies have become available in which an agnostic search of the genome is performed using multiple variant markers.2 This method aims to identify common variants associated with LDD. We have performed the first GWA meta-analysis of LDD and explored the role of epigenetic influence at the most highly associated marker.3 We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, computed tomographic scan and magnetic resonance imaging) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap vs2. This study of 4,600 individuals identified 4 single nucleotide polymorphisms with p < 5 × 10-8, the threshold set for genome-wide significance. We identified a variant in the PARK2 gene ( p = 2.8 × 10-8) associated with LDD. Examination of methylation using the Illumina 450k chip showed differential methylation at one CpG island of the PARK2 promoter in a subset of subjects from TwinsUK (β = 8.74 × 10-4, p = 0.006). This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD but has been reported in juvenile Parkinson disease as well as tumor development. The gene encodes a protein called parkin, is a component of the ubiquitin ligase complex, targeting effete proteins for removal. This study highlights how GWAS is useful at identifying new pathways of pathology—much needed in this difficult to study tissue. In addition, the limitations of the candidate gene approach are increasingly recognized.4 This work required further independent replication, and epigenetic factors are also to be explored further, given that so little of the estimated heritability is accounted for by the genetic variants identified thus far. Finally, ongoing work refining phenotypes will allow large consortia to amass the sample sizes required for robust findings. Disclosure of Interest None declared References Eskola PJ, Lemmelä S, Kjaer P, et al. Genetic association studies in lumbar disc degeneration: a systematic review. PLoS ONE 2012;7(11):e49995 Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet 2012;90(1):7–24 Williams FM, Bansal AT, van Meurs JB, et al. Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects. Ann Rheum Dis 2013;72(7):1141–1148 Richards JB, Kavvoura FK, Rivadeneira F, et al; Genetic Factors for Osteoporosis Consortium. Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 2009;151(8):528–537