Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects

Spine J. 2013 Oct;13(10):1309-20. doi: 10.1016/j.spinee.2013.05.019. Epub 2013 Jun 21.


Background context: Although the influence of genetics on the process of disc degeneration is well recognized, in recently published studies, there is a wide variation in the race and selection criteria for such study populations. More importantly, the radiographic features of disc degeneration that are selected to represent the disc degeneration phenotype are variable in these studies. The study presented here evaluates the association between single nucleotide polymorphisms (SNPs) of candidate genes and three distinct radiographic features that can be defined as the degenerative disc disease (DDD) phenotype.

Purpose: The study objectives were to examine the allelic diversity of 58 SNPs related to 35 candidate genes related to lumbar DDD, to evaluate the association in a hitherto unevaluated ethnic Indian population that represents more than one-sixth of the world population, and to analyze how genetic associations can vary in the same study subjects with the choice of phenotype.

Study design: A cross-sectional, case-control study of an ethnic Indian population was carried out.

Methods: Fifty-eight SNPs in 35 potential candidate genes were evaluated in 342 subjects and the associations were analyzed against three highly specific markers for DDD, namely disc degeneration by Pfirrmann grading, end-plate damage evaluated by total end-plate damage score, and annular tears evaluated by disc herniations and hyperintense zones. Genotyping of cases and controls was performed on a genome-wide SNP array to identify potential associated disease loci. The results from the genome-wide SNP array were then used to facilitate SNP selection and genotype validation was conducted using Sequenom-based genotyping.

Results: Eleven of the 58 SNPs provided evidence of association with one of the phenotypes. For annular tears, rs1042631 SNP of AGC1 and rs467691 SNP of ADAMTS5 were highly significantly associated (p<.01) and SNPs in NGFB, IL1B, IL18RAP, and MMP10 were also significantly associated (p<.05). The rs4076018 SNP of NGFB was highly significant (p<.01) and rs2292657 SNP of GLI1 was significantly (p<.05) correlated to disc degeneration. For end-plate damage, the rs2252070 SNP of MMP 13 showed a significant association (p<.05). Previously associated genes such as COL 9, SKT, CHST 3, CILP, IGFR, SOXp, BMP, MMP 2-12, ADH2, IL1RN, and COX2 were not significantly associated and new associations (NGFB and GLI1) were identified. The validity of all the associations was found to be phenotype dependent.

Conclusions: For the first time, genetic associations with DDD have been performed in an Indian population. Apart from identifying new associations, the highlight of the study was that in the same study population with DDD, SNP associations completely changed when different radiographic features were used to define the DDD phenotype. Our study results therefore indicate that standardization of the phenotypes chosen to study the genetics of disc degeneration is essential and should be strongly considered before planning genetic association studies.

Keywords: Disc degeneration; Genetic association; Phenotype; Single nucleotide Polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Asian Continental Ancestry Group / genetics
  • Case-Control Studies
  • Cross-Sectional Studies
  • Female
  • Genetic Association Studies / methods*
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • India
  • Intervertebral Disc Degeneration / diagnostic imaging*
  • Intervertebral Disc Degeneration / genetics*
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Radiography
  • Young Adult