Blood cell traits, including hemoglobin level, red blood cell (RBC), white blood cell (WBC), and platelet counts, are important intermediate clinical phenotypes for a variety of cardiovascular, hematologic, oncologic, immunologic and infectious disease. The distributions of these traits differ considerably across ethnicities. For example, further insight into the genetic determinants of ethnic neutropenia in African Americans (AA) may have implications for health disparities in risk of HIV infection, sickle cell disease severity or mobilization of neutrophils or hematopoietic stem cells in cancer patients. Our preliminary data similarly suggest important differences in the distribution of blood cell traits in Hispanics compared to non-Hispanic whites. Therefore, the proposed studies are likely to have direct clinical impact by providing new avenues for treatment, particularly for minority patients with low blood counts (Personalized Medicine), and illuminating new mechanisms by which genetic factors related to ethnic differences in blood cell counts contribute to U.S. health disparities fo risk of chronic inflammatory and thrombotic diseases. Despite the importance of genetic factors in explaining variation in blood cell traits, there remains a huge gap in our knowledge of the contribution of specific loci to these traits among U.S. minorities. Coincidentally, multiethnic GWAS has been recognized as more powerful for gene mapping by the genetics community. However, there are very few sequencing-aided GWAS for blood cell traits in ancestrally diverse populations, and none in Hispanics/Latinos (HLs). Consequently, innovative methods are needed to study blood cell traits in multiethnic cohorts, particularly those recently admixed such as AA and HL, which have been under- represented in prior GWAS. The first attempts to map genes for blood cell traits in AA did not incorporate sequence based African specific content into the imputation, were limited in sample size, and did not accounted for local ancestry, mainly due to the lack of available methods and resources. Importantly, no GWAS have been conducted in HL for blood cell traits. For the proposed studies, our team has now assembled a new, larger collection of AA (n~34K), HL (n~26K) and Europeans (EU) (n~30K), and will leverage our recent methodological advances in imputation, local ancestry inference, and association analysis to increase our knowledge of blood cell trait genetics. We propose the following Aims.
Aim 1. Map genes for blood cell traits in AA (n~34K) accounting for local ancestry.
Aim 2. Conduct the first sequencing-aided GWAS of blood cell traits in HL (n~26K) accounting for 3- way local ancestry.
Aim 3. Meta-analyze across multi-ethnic datasets, annotate and validate novel association signals.

Public Health Relevance

Blood cell traits, including red blood cell count (RBC), hemoglobin, white blood cell count (WBC) and platelet count, are important intermediate clinical phenotypes for a variety of cardiovascular, hematologic, oncogenic, immunologic and infectious diseases. However, there are very few sequencing-aided GWASs for blood cell traits in ancestrally diverse populations, and none in Hispanics/Latinos. We will study genetic mechanisms underlying blood cell traits in multi-ethnic cohorts, in particular admixed, under-represented U.S. minority populations such as African Americans and Hispanics/Latinos.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL129132-04
Application #
9658547
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Qasba, Pankaj
Project Start
2016-07-15
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2021-02-28
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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