Several studies have shown that rare and common genetic variants influence complex traits as well as the human lifespan and healthspan, and that these variants differ in frequency and importance across populations. What has remained underexplored is the synergistic effect of these variants, their contextual effects, as well as the variability of these types of effects across populations and throughout the lifespan and healthspan. We propose to further investigate the complexity of this variation using the UK Biobank. First, we will identify fine-scale population structure, using a combination of new and established population genetics methods, and study genetic variability among these groups. We are also proposing to develop new statistical methods for understanding the contribution of environmental and clinical context of both rare and common genetic variants to disease risk, in these diverse populations and across the healthspan. Lastly, we will use the UK Biobank cohort to identify novel rare variants as well as validate our analyses of other datasets, such as our in-house longevity cohort (n=2,487), aging study (n ~1500), and the All of Us dataset.
