Identification of common and rare genetic risk factors for lumbar disc degeneration

Abstract

Lumbar disc degeneration (LDD) is a major etiological risk factor for low back pain (LBP), which is a common and disabling condition, affecting 80% of the general population at some time in life. LDD has been reported to have a substantial genetic component with up to 70% heritability, and to be associated with numerous risk factors including age, body mass index (BMI), heavy lifting, smoking cigarettes and occupation. This study aimed to identify common and rare genetic variants associated with LDD in Southern Chinese population. We first evaluated systemically and classified the different magnetic resonance imaging (MRI) features of LDD. Analyses showed that lumbar disc MRI features separate into two groups with different patterns of risk factor associations. The correlation and association results of the phenotypes were integrated to generate a combined phenotype scoring system for genetic study. Both single and combined MRI phenotypes were used for genome-wide association study in 2,200 subjects with Southern Chinese origin, among which we selected 25% samples (n=715) from the tails of the phenotype distributions and performed whole exome sequencing. Both hypothesis-free and hypothesis-driven strategies were used in the analyses. We identified a genome-wide significant signal in Chromosome 15 (rs1902430, P = 1.57e-8). Two genes, SCG3 and LYSMD2, were significant in this region. An additional low frequency missense variant, which only exists in LDD cases, was further identified in SCG3 from whole exome sequencing analysis (rs146162352, P = 0.005). Furthermore, functional gene-set analyses for suggestive associated genes (P < 1e-5) indicated potential relevance of interleukin pathways, integrin pathway and signaling pathway in LDD. For previously reported LDD-associated genes, 8 genes, including ACAN, COL9A2, COL9A3, CHST3, MMP2, ADAMTS5, IL1RN, GLI1, were nominally significant. Moreover, to improve the power of genetic studies of LDD, cross disorder analyses were employed to leverage on pleiotropy with bone mineral density and osteoarthritis. Two loci in gene KCND3 and SPC24 were identified to be pleiotropic between BMD and LDD (SFDR q<0.05). Meanwhile, the other two loci were associated with both OA and LDD, one is located in gene DPP10 and the other one is in intergenic region (SFDR q<0.05). Together with genome-wide association and whole exome sequencing analyses, this study presents a catalog of both common and rare genetic variants associated with lumbar disc degeneration in Southern Chinese population.