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Background: The etiology of degenerative disc disease (DDD) is complex and includes genetic, gender, age, environment and traumatic factors. Obvious relatedness of DDD patients has been documented. Genetic factors account for 75% of the risk of DDD and although many genes have been associated with DDD, no specific marker genes have been found. Therefore, we will establish a biological sample library and database of DDD patients who have a family history of the disease and who require surgical treatment. To identify pathogenic DDD genes, we will screen the patient database for genes that contain polymorphisms and/or are differentially expressed. Methods/Design: This is a single-center, case-control study, which will be performed in Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, China. A total of 2,000 subjects will be prospectively collected from the wards and clinics of Shanghai First People's Hospital. These patients will consist of 1,000 DDD patients with a family history, 500 DDD patients without a family history, and 500 normal controls. Blood or intervertebral disc tissue samples will be collected. Total RNA will be sequenced to identify differentially expressed genes. Genome-wide association analysis will be performed using high-throughput microarrays and single nucleotide polymorphism microarrays and pooling (SNP-MAP). The primary outcome measure of this study will be the percentage of differentially expressed genes in DDD patients with or without a family history. The secondary outcome measures will be sequence variation in differentially expressed genes, SNP genotyping, routine liver and kidney function tests, routine blood tests, routine urine tests, and morphology of degenerated spinal discs. Discussion: This study aims to identify the pathological and physiological risk factors of DDD from the perspective of genetics by screening for genes that are differentially expressed in DDD and to correlate them with DDD, and to identify precise molecular targets for drug development and diagnostics. Trial registration: The study protocol was registered in Chinese Clinical Trial Registry (registration number: ChiCTR-COC-16009617) on October 10 th , 2016. Ethics: This study has been approved by Scientific Research Project Ethics Committee, Shanghai First People's Hospital, China (approval number: 2016KY166-2) and will be performed in strict accordance with the Declaration of Helsinki formulated by the World Medical Association. Informed consent: Written informed consent regarding study protocol and treatment procedure will be obtained prior to involvement in the clinical trial.