Chronic Post-amputation Pain (cPAP) is a major unsolved healthcare problem. Every year, Veterans Health Administration (VHA) hospitals perform 7,000 amputations and civilian hospitals perform approximately 115,000 amputations. Between 50 and 90% of Amputees will suffer from cPAP, with impaired psychological well-being, physical disability, and a substantially lower quality of life in those patients affected, in addition to the cost to society at large. Even novel surgical methods such as regenerative peripheral nerve interface surgery can only modestly reduce, but not prevent, cPAP. Once cPAP has developed, treatment is very difficult with few therapeutic options. Despite the high clinical relevance, there are still critical gaps in our knowledge of cPAP and its pathophysiology. Our proposal is focused on addressing three of these gaps using the framework of the Million Veteran Program (MVP). The first Specific Aim is to describe the demographics of the MVP Amputee cohort, and the incidence of cPAP in that cohort. This will be defined as point prevalence 9 (± 3) months after amputation. The complementary outcome measures are the incidence and severity of cPAP over time, as well as 1- and 5-year mortality. This will give us a solid understanding of the Amputee cohort within MVP. In addition, we will describe the perioperative care these patients received around their amputation, and the access to care they had after surgery, and whether these factors are associated with the development of cPAP. At completion of Specific Aim 1, we will have created a valuable MVP-specific phenotype for well-conducted genetic studies, which will also facilitate studies by other researchers. We will have also assessed the patterns of practice, the access to care, and the resulting time-course and severity of cPAP in MVP patients. The second, and central, Specific Aim of this proposal is to identify genetic variants that are associated with cPAP risk in MVP patients. This will serve three purposes: first, it will allow us to better understand the genetic basis for individual risk to develop cPAP; second, it will allow us to describe the congruence of genetic risk factors between cPAP and diagnoses which we know to influence pain conditions, in particular chronic non- cPAP pain, anxiety, depression, PTSD, schizophrenia and substance use disorders; and third, this Aim will shed light on biological-pathway based risk factors specific for cPAP, which may help identify therapeutic or preventive candidate therapies going forward. At completion of Specific Aim 2, we will have characterized the influence of genetic factors on the occurrence of cPAP while accounting for genetic risks of highly correlated psychosocial risks. The third Specific Aim of this proposal is to examine patient-specific health characteristics, including psychosocial factors and Social Determinants of Health (SDOH). Despite strong evidence in other domains, the relationship between psychosocial factors, ...