Identification of genetic risk factors in human idiopathic scoliosis
Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood, affecting about 3% of the population worldwide. In this condition the spine twists, rather than growing straight, during the adolescent growth spurt. Severe AIS risks pulmonary dysfunction and pain later in life, and consequently many states have implemented mandatory school screening programs so that early treatment can be initiated. Typically AIS is treated initially by bracing to limit progression of the deformity. Surgery is indicated when bracing fails and involves insertion of metal implants and screws to hold the spinal column straight. AIS surgeries are estimated to cost 3 billion USD annually, a number that is rising rapidly over other health care costs due to the increasing costs of metal implants. Thus while the overall health burden of AIS is significant and increasing here in the United States and worldwide, its underlying pathogenesis is largely unknown.
We are using genetic approaches to understand the causes of AIS, a complex disease with strong heritability. In this Program we are leading a project to apply exome-focused approaches including genome-wide association studies (GWAS) and whole genome sequencing to large AIS populations ascertained in our institution and around the world. We are also extending prior findings by meta-analysis of existing GWAS, an effort that we are coordinating through the International Scoliosis Genetics Consortium (ICSG), a group dedicated to genetic discovery through multidisciplinary collaborations. We are partnering with the Genomics project to integrate our discoveries with a new understanding of the genetic regulatory landscape of the developing spine. We are also partnering with the Zebrafish project to model the effects of AIS risk factors, and to test new candidate genes identified in that system. Our combined program of human molecular genetics, large-scale genomics, and model system genome editing represents a new paradigm not only for AIS research, but also for complex human diseases generally. These synergistic interactions will drive mechanistic understanding of spine development, of AIS pathogenesis specifically, and will stimulate new insights into potential preventions.