Kuru was the first documented epidemic of prion disease in humans. It took place in a restricted region of the Papua New Guinea Highlands during the twentieth century, with the final cases occurring in the first decade of the twenty-first century. Over 2,700 deaths were recorded in the period 1957-2004 when surveillance was carried out in the region. The epidemic impacted greatly upon affected communities as a result of its high incidence, and its association with practices of sorcery in the region. This project sought to further understand the genetic impact of kuru using a genotyped data from 943 individuals from 21 ethno-linguistic groups in the Eastern Highlands region of Papua New Guinea (EHPNG). Analysis was conducted to classify the population structure in the region using a suite of population genetic tools. Linguistic group membership was the strongest descriptor of population genetic structure in the region, informing experimental design in subsequent analyses. A drop in genetic diversity was observed in the most affected South Fore linguistic group during the course of the epidemic, confirming that the drastic impact on the ground left a genetic signature. A new tool (Chromomatcher) was developed and incorporated in attempts to find genetic variants under positive selection during the kuru epidemic. Several genetic variants show evidence of being under recent positive-selection. Finally, polygenic architecture of prion diseases was investigated revealing a significant polygenic architecture for sporadic Creutzfeldt–Jakob disease (sCJD) with a substantial portion shared with variant Creutzfeldt–Jakob disease. No shared architecture was observed between sCJD and kuru, reflecting the challenges of applying this technology to under-studied populations.