Genetics of Osteoarthritis Susceptibility, Heterogeneity and Progression

The societal and patient-centered impacts of osteoarthritis (OA) are profound – total costs for OA treatment in the US exceed $486 billion annually. OA management is limited to symptom management (e.g., pain, inflammation). As such, OA often progresses to end-stage at which time only surgical options are available in the form of total joint replacement (TJR). Alarmingly the prevalence of moderate-severe functional limitations 2- 5 years post-surgery remains high (>30%) post TJR. OA is a heritable trait which we recently estimated to be as high as 50% in Hispanic Veterans in the Million Veteran Program (MVP). Despite two recent seminal manuscripts on the genetics of OA, gaps remain in our understanding of the role of specific genetic variation to OA susceptibility, heterogeneity, and progression. These gaps impede development of personalized approaches essential for guiding OA risk reduction and therapeutic intervention. Previous research has demonstrated OA joint site reflects underlying etiological heterogeneity demonstrate distinct genetic region associated with OA at specific joint sites. Similarly, women are more likely to develop OA however, the MVP is comprised of predominantly male Veterans limiting power to identify genetic variants which may be sex specific. Our overall goal is to decipher the genetics of OA susceptibility, heterogeneity, and progression. Toward this goal in Aim 1, we identify new and fine-map known genetic loci associated with susceptibility to OA and total hip/ total knee arthroplasty (THA/TKA); in Aim 2, we disentangle OA heterogeneity by identifying distinct genetic variation associated with OA at specific joint sites; and in Aim 3, we identify sexually dimorphic genetic variants associated with OA in women. We will identify genetic regions associated with OA susceptibility, heterogeneity and progression enabling risk stratification and in turn advancing patient care.