Linkage analysis on familial early onset degenerative disc disease

Abstract

Introduction. Low back pain is commonly caused by degenerative disc disease (DDD). While the etiology of DDD is not known, recent evidence from case-association studies suggests that genetic factors, such as polymorphisms in COL9A2, COL9A3, COL1A1, VDR, AGC1, MMP3, CILP and IL1, play a significant role. Family-based linkage analysis has the ability to discover new candidate genes without prior biological knowledge. Success of linkage analysis is based on the ability to identify a discriminating phenotype and the recruitment of large families. Method. Southern Chinese subjects with low back pain and early-onset DDD, defined as MRI-proven disc degeneration or herniation occurring under 30 years of age, were recruited into the study together with their family members. T2-weighted sagittal MRI of the whole spine were performed, and their blood were taken for DNA isolation. MRI were graded using Schneiderman’s classification. The initial genomewide linkage mapping was based on the ABI PRISM Human Mapping Set with 400 microsatellite markers at an average resolution of 10 cM. Besides Schneiderman’s score, which does not differentiate between age-related changes and DDD, we have also created a novel age-adjusted scoring system to account for the effect of age on DDD status. Result. Altogether 18 families with 126 individuals were recruited in this study. The families were screened and chosen based on the involvement of several generations and presence of multiple members with early-onset DDD. After data analysis, candidate regions with suggestive linkage were identified in chromosomes 1, 5, 8, 10, 14, 20. Discussion. This is the first, large-scale genome wide linkage analysis study for subjects with early-onset DDD, using a clear phenotype definition for both cases and controls. It has revealed a number of promising loci for further study. Work is on-going to perform fine-mapping of these regions in order to identify possible candidate genes for further analysis.