Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects

Abstract

Objective: Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD.

Methods: We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2.

Results: This study of 4600 individuals identified four 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. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (β=8.74×10(-4), p=0.006).

Conclusions: LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. 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 and further functional work is needed on this hitherto unsuspected pathway.

Keywords: Gene Polymorphism; Low Back Pain; Magnetic Resonance Imaging.

Figure 1

Quantile–quantile plot of observed versus expected distribution of p values for the genome-wide association (GWA) meta-analysis. The plots show GWA meta-analysis quantile–quantile plot of observed against expected results, unadjusted for covariates.

Figure 2

Manhattan plot for meta-analysis of unadjusted genome-wide association results. Plot shows combined results for the five studies included in the meta-analysis, unadjusted results. The blue and red horizontal lines mark the levels of suggestive and likely significance, respectively.

Figure 3

Forest plot of rs926849 in PARK2 unadjusted for covariates. The contribution of the studies included in the meta-analysis is shown in this fixed effects model. The C allele is considered. Heterogeneity, I²=0%; p(Q)=0.67. TE, treatment effect; seTE, standard error treatment effect.

Figure 4

Regional plot of association results and recombination rates for the PARK2 gene, unadjusted results. −log₁₀ p values (y-axis) of the single nucleotide polymorphisms (SNPs) are shown according to their chromosomal positions (x-axis) with lead SNP shown as a purple diamond. The colour intensity of each symbol depicting an SNP reflects the extent of LD with the rs926849, coloured red (r²>0.8) through to blue (r²<0.2). Genetic recombination rates (cM/Mb), estimated using HapMap CEU samples, are shown with a light blue line. Physical positions are based on build 36 (NCBI) of the human genome. Also shown are the relative positions of genes mapping to the region of association. Genes have been redrawn to show the relative positions and, therefore, the maps are not to physical scale.