Low back pain and sciatica are the most common musculoskeletal complaints. Even though secondary factors such as environmental and anthropometric risk factors contribute to intervertebral disc disease, genetic factors may play a significant role in the pathogenesis of the disease. The role of genetic factors is supported by our recent findings: We showed that a tryptophan for glutamine substitution in the alpha2 chain of collagen IX co- segregated with sciatica and intervertebral disc disease in four families with a LOD score of 4.5. Subsequent linkage disequilibrium analysis conditional on linkage gave an additional LOD score of 7.1. Thus, the joint lod score is 11.6 (4.5 + 7.1). In addition, we identified another tryptophan mutation in collagen IX (alpha3 chain). The mutation is significantly associated with the disease (p value: 0.000013) and it increases the relative risk for the disease by a factor of 2.6 (95 percent confidence interval, 1.6 to 4.3). The Specific Aims of the present proposal are: (1) To use the new sequence data from the genes and the new protocols we have developed to analyze DNA from 150 probands with sciatica and 100 probands that have had surgery for herniated discs for mutations in eight candidate genes: three genes for collagen IX (COL9A1, COL9A2 and COL9A3), three genes for collagen XI (COL11A1, COL11A2 and COL11A3 or COL2A1), the aggrecan gene, and the gene for link protein. (2) To evaluate the significance of the sequence variations as disease-causing mutations by analyzing the family members of the probands and non-symptomatic individuals for the presence of the sequence variations. (3) To distinguish neutral polymorphisms from mutations that cause or predispose to intervertebral disc disease, we will also synthesize the normal and mutated recombinant human proteins and determine whether the mutations alter the biological function of collagens IX and XI by assays that include (a) the thermostability of triple helices of the collagens; (b) binding to collagen II; and (c) potential of the collagen IX and XI to alter the self-assembly of collagen II into fibrils in vitro. (4) To do genome-wide screen on 100 affected sib pairs and/or families to identify additional loci for intervertebral disc disease.