Research

Genome-wide association studies (GWAS) have been extremely successful at discovering genetic variants underlying many diseases. There is a great deal of interest in translating these findings to estimate an individual’s genetic risk for disease (so-called polygenic risk) to be used in the clinic for early prevention and intervention. Unfortunately, the predictive ability of polygenic risk prediction is at present limited and varies as a function of ancestry. This is because both variant discovery and prediction accuracy depend on the genetic variation underlying complex traits, which in turn is shaped by population history. We combine theoretical modeling and analysis of empirical data to study these relationships with the long-term goal to improve our understanding of the genetic basis of disease risk in diverse populations. We have several ongoing projects that fall under the following themes:

Admixture is a ubiquitous feature of human history. It is also a powerful evolutionary force that has played an important role in shaping human phenotypic variation. We use population genetic theory to study the non-equilibrium behavior of complex trait variation under realistic models of human admixture. We seek to understand the advantages and limitations of genetic analyses (e.g. association studies, fine-mapping, and polygenic risk prediction) in admixed populations.

South Asia is culturally one of the most diverse regions of the world, with 1000s of ethno-linguistic groups. These cultural groups often coincide with genetic clustering due to the practice of endogamy that has been around for centuries. Some populations in South Asia also have some of the highest rates of consanguinity (close-kin unions) in the world. We study the extent to which these practices have shaped the distribution of disease risk in South Asia. In doing so, we seek to understand the link between common and rare diseases and the contribution of recessive variation to complex traits.

Mitochondrial DNA (mtDNA) is a small but functionally important piece of DNA residing in the mitochondria of all eukaryotic cells. The evolutionary forces that shape mtDNA variation differ considerably from the nuclear genome. MtDNA has a high mutation rate and is transmitted maternally, which means it has one fourth the effective population size of autosomal loci. Within an individual, cells vary considerably in how many mtDNA they carry (e.g 100 copies/neutrophil - 100k copies/oocyte). These copies can accumulate mutations throughout the life of the individual, increasing the risk of disease. We study the processes that shape mtDNA variation both within and among individuals and how this variation contributes to disease variation.