2024-25 Pilot Projects Funded
Project Title: Complete reference genomes of diverse African populations to increase representation in human genomics, and reduce health disparities
PIs: Glennis Logsdon, PhD
Project Summary:
Since its initial release two decades ago, the human reference genome has revolutionized studies of human genomics and led to fundamental discoveries in both human variation and evolution. This draft sequence consisted of a mosaic representation of individual haplotypes and contained ~200 gaps that span ~6.7% of the human genome. Recently, I and others in the Telomere-to-Telomere (T2T) generated the first complete sequence of a human genome, which filled the gaps of the current reference genome and enabled the discovery of ~100 new genes. While these milestones represent major achievements, neither of these reference genomes captures the full extent of human diversity. Previous studies have shown that these reference genomes are missing dozens of megabases of structurally variant sequences that are polymorphic in the population and may contribute to disease. The lack of representation of these variants within the human reference genome has led to health disparities that prevent effective treatment and pharmaceutical development for diverse populations on a global scale. The proposed project aims to address this issue by generating a set of complete reference genomes from individuals with African ancestry, which will complement existing reference genomes and improve representation of diverse individuals in human genomics. Our work will generate valuable resources for the broader scientific community which will improve representation of diverse Africans in human genomics and improve health for all.
Project Title: Disparities in cardiovascular disease: disentangling ancestry from social determinants of health
PIs: Rajat Deo, MD and Hongzhe Li, PhD
Project Summary:
Black Americans are much more likely to develop cardiovascular events including strokes, heart failure, sudden cardiac death and other fatal cardiovascular diseases than White Americans. Black Americans are subject to social determinants of health (SDOH) that play clear roles in leading to clinical disease. Selective pressure from infectious diseases in sub-Saharan Africa has enriched for a variety of protective genetic adaptations affecting blood cells and proteins. These protective variants, which are highly prevalent in Black Americans, are also associated with numerous chronic conditions. The greater genetic diversity in populations of African ancestry, and millennia of genetic drift and selection, have created a genetic milieu that necessarily differs from other populations in ways that are not yet known. We seek to understand the contributions of genetics and social determinants of health on cardiovascular risk and subclinical measurements in Black Americans. The results from our analyses aim to assess whether social determinants of health, more than genetic ancestry, are the major drivers of the well-established disparities in cardiovascular health.
2023-24 Pilot Project Funded
Project Title: The Role of Gene-by-Environment Interactions on Asthma Disparities Among Adults in Philadelphia
PIs: Blanca Himes, PhD / Wei-Tang Hwang, PhD / Patrick Gleeson, MD
Project Summary:
Asthma, a chronic disease that manifests as airway hyperresponsiveness to specific environmental stimuli, affects over 20 million American adults and disproportionately affects racial and ethnic minority groups. Genetic, environmental, and social factors are known to contribute to asthma, but the complex interactions among these variables that underlie asthma symptoms and lead to disparities are not well understood. Biobanks that are derived from real-world populations represented in Electronic Health Records (EHRs) are invaluable to conduct genetics studies because they capture a large number of diverse people. We and others have identified many loci associated with asthma in diverse populations via genome-wide association and whole genome sequencing studies. In addition, we have identified individual- and area-level factors that are associated with asthma using EHRs linked to rich and diverse sources of social, economic, and environmental variables. In this proposal, we will leverage the Penn Medicine BioBank to conduct asthma gene-by-environment studies in Black and White adults that live in the greater Philadelphia area, a region whose residents suffer a disproportionate burden of pollution exposure. Our aims are to 1) Identify shared and population-specific genetic loci that contribute to adult asthma risk in Black and White PMBB subjects; 2) Determine which asthma associations differ according to air pollution exposure by conducting a gene-by-environment analysis; and 3) Select associations with evidence for a functional role in asthma and/or responses to pollution by applying a multi-omics integrative strategy. Our study will identify asthma-associated loci in Black and White adults whose effect is modified by air pollution exposure and support future grant applications related to asthma disparities in which the role of genetics and air pollution can be addressed simultaneously. The air pollution data we link to the Penn Medicine BioBank will be a helpful resource for other investigators to conduct gene-by-environment studies of other diseases.
2022-23 Pilot Projects Funded
Project Title: Identifying SNPs associated with volumetric breast density among Black women
PIs: Anne Marie McCarthy, PhD; Shefali Setia Verma, PhD and Despina Kantos, PhD
Project Summary:
Breast cancer is the leading cause of cancer death among Black women in the U.S. Black women are diagnosed at later stages than White women and are more likely to be diagnosed with triple negative breast cancer, which has less effective treatment options and poorer prognosis than other subtypes. Given these disease characteristics, improvements in early detection are critical to reduce health disparities in breast cancer mortality. Breast density is one of the strongest known risk factors for breast cancer and has a strong genetic component. Women with dense breasts may benefit from earlier, more frequent mammography and from supplemental screening with breast ultrasound or breast MRI. We have developed a novel, quantitative algorithm to measure volumetric breast density from 3D mammograms, which has been shown to better quantify breast density and more strongly associated with breast cancer risk than conventional breast density measures. Identification of SNPs associated with breast density may point to pathways that underlie breast density and breast cancer risk, improve risk assessment, and enable estimation of risk due to breast density prior to screening initiation. We propose to generate a polygenic risk score for breast density leveraging the Penn Medicine Biobank and evaluate whether this risk score is associated with breast cancer risk.
Project Title: Examination of Genetic and Environmental Factors Affecting Thyroid function in populations of African Ancestry
PIs: Anne R. Cappola MD, ScM; Alisha N. Wade MBBS, DPhil; and Michèle Ramsay, PhD
Project Summary:
Thyroid dysfunction affects approximately 10% of the population and is diagnosed when thyroid stimulating hormone (TSH) is outside of reference ranges established in White individuals. Observational studies in Black individuals have reported a shift in the TSH distribution to the left compared with White individuals. The clinical implication of this shift towards lower values is overdiagnosis and overtreatment of hyperthyroidism and underdiagnosis and inadequate therapy of hypothyroidism in Black individuals. The cause of this distribution shift is unknown. We hypothesize that it is due to ancestry-related differences in the genomic determinants of thyroid function. To date, genomic studies of thyroid function have been exclusively conducted in populations of European ancestry, with no analyses in African ancestry populations. Although 40-60% of thyroid function is thought to be heritable, genetic variants from European ancestry populations explain only a third of the variance in TSH and a fifth of the variance in the thyroid hormone free thyroxine, suggesting that additional relevant genes are yet to be described. In our preliminary data, we demonstrate for the first time that strong and consistent associations between PDE8B and TSH in large European meta-analyses and in individuals of European descent in the Penn and Vanderbilt Biobanks are not replicated in Black South Africans and individuals of genetically-inferred African ancestry from those biobanks. We further identified associations with novel variants in each of our African ancestry populations. Larger studies with greater statistical power are required to understand which variants are critical to the regulation of thyroid function in those of African descent. We will capitalize on the significant genetic variation and low linkage disequilibrium in populations on the African continent to determine genomic variants associated with thyroid function indices in African- ancestry individuals. We will use samples from the NIH-funded H3Africa Africa Wits-INDEPTH Partnership for the study of genomic and environmental risk factors for cardiometabolic disease in Africans (AWI-Gen) study as a discovery cohort and replicate our findings in African-ancestry individuals in the All of Us study in the United States, two cohorts living in very different environments. This project will address a long-ignored health disparity in thyroid function assessment by race, inform the clinical diagnosis of thyroid dysfunction in Black individuals, and contribute more broadly to knowledge of thyroid regulation which has implications for health of people of all ancestries.
2021-22 Pilot Project Funded
Project Title: Assessing and Mitigating the Disparate Impact of COVID-19 on Historically Oppressed Populations in the Greater Philadelphia Region.
PIs: Carolyn C. Cannuscio ScD and Frederic D. Bushman, PhD
Project Summary:
The overarching goal of this project is to eliminate health disparities through a genomics-augmented approach to contact tracing and pandemic control. We propose to integrate the promising tools of genomic epidemiology and early detection in outbreaks in populations from Philadelphia. The aims of this proposal are to: 1) integrate SARS-CoV-2 whole genome sequencing (WGS) with contact tracing data to understand transmission dynamics, identify COVID-19 variants of concern, and improve outbreak control, and 2) identify social and biological determinants of COVID-19 outcomes in a diverse cohort of Philadelphians. Upon completion of the proposed aims, we will have developed a public health model that can be rapidly deployed to control SARS-CoV-2 transmission in high-risk communities, and to stem future epidemics. We will also have identified social and biological risk factors associated with persistent COVID-19 symptoms.