Project Details
Description
Title: Leveraging human evolutionary history to improve our fundamental understanding
of complex disease architecture
Abstract: The overarching goal of this research is to improve the applicability of genetic risk
predictions within and across human populations by leveraging recent advances in our
understanding of human evolutionary history. In Aim 1, I will carry out empirically-guided
simulations to investigate how fine-scale substructure in large genome-wide association studies
(GWAS; e.g. UK Biobank) biases our inference of complex trait architecture and polygenic risk
score prediction. I will leverage these findings to develop statistical and computational tools to
correct for such biases. In Aim 2, I will investigate whether recent admixture in humans generates
incompatibilities between mitochondrial and nuclear DNA in African Americans. To test this, I will
analyze genetic and electronic health record data from the ethnically diverse Penn Medicine
Biobank to test whether mito-nuclear discordance—degree of ancestry divergence between
mitochondrial and nuclear genomes—is associated with the risk of diseases common among
African Americans. Additionally, I will test for selection against mito-nuclear incompatibilities in
recently admixed populations. In Aim 3, I will investigate how the practice of endogamy and
consanguinity among Pakistanis shapes their disease risk architecture. I will further evaluate the
ability and limitations of currently used GWAS methods, which are typically modeled after outbred
populations, to infer disease architecture given the complex population structure in Pakistanis. I
will improve upon these methods, thereby making GWAS more widely applicable to a diverse set
of people. Each of my three aims is independent, yet together they will lead to improvements in
diagnosis, treatment, and prevention of human diseases—the overarching mission of the NIGMS.
I will learn the skills needed to accomplish these aims with the help of my advisory committee,
comprising of Drs. Iain Mathieson, Sarah Tishkoff, Doug Wallace, and Marilyn Ritchie, who are
world-class leaders in genetics research. With the training plan that I have outlined and the
resources at the University of Pennsylvania, I am confident that the K99 award will help me
achieve my goal of becoming an independent scientist in the field of statistical genetics.
Status | Finished |
---|---|
Effective start/end date | 8/1/21 → 7/31/23 |
Funding
- National Institute of General Medical Sciences: $90,638.00
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