Asthma is a complex disease where the interplay between genetic factors and environmental exposures has significant influence on susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry, but relatively few studies have focused on this underrepresented minority group. Genome-wide association studies (GWAS) have revolutionized gene discovery for multiple complex traits, but implementation of the next step in gene discovery following GWAS of asthma among populations of African descent requires considerations unique to this ethnic group, including adequate sample sizes, population stratification due to admixture, and perhaps most importantly, an approach that recognizes that the current coverage of common variation both in the public database and particularly on commercially available SNP chips is inadequate to detect true genetic association among African admixed populations. In our own GWAS on 1,000 African American asthma cases and controls from Baltimore-Washington, D.C. and 1,000 African Caribbean asthmatics and their family members from Barbados, we have identified suggestive associations for which replication is not observed in populations of European descent, supporting the hypothesis that populations of African descent may carry unique susceptibility loci. We have forged a collaboration of investigators representing 12,000 DNA samples from well-characterized African American and African Caribbean asthmatic patients and healthy controls and/or family members from which six studies (5,000 samples) have GWAS data available for meta-analysis and seven populations (>7,000 samples) are available for replication. In this application, we propose four specific aims: (i) we will leverage discoveries in the 1,000 Genomes Project and data-mine for novel SNPs in African and African admixed populations develop a custom, African-ancestry gene-centric 200K SNP genotyping array ('African Power Chip') to complement current, commercially available GWAS chips, for which common and rare variants are not adequately tagged by the existing SNPs, and thereby facilitate GWAS studies on populations of African descent;(ii) we will perform genotyping on DNA samples with existing GWAS data among the 'Consortium on Asthma among African-ancestry Populations in the Americas'(CAAPA) and test for associations with asthma, followed by;(iii) in-depth analyses including imputation-based association mapping of asthma loci, copy number variant (CNV) analyses, and admixture mapping;and (iv) replicate the most significant associations in independent samples available through CAAPA. Results from these studies will lead to substantial advancements in the technology available for identifying genes relevant to disease for what is one of the most underrepresented minorities in biomedical research, African ancestry populations, and will generate deliverables to the scientific community at large, both as an invaluable database and as a validated SNP chip.

Public Health Relevance

In this study we will take advantage of discoveries in the 1000 Genomes Project and select genetic variants that best represent the genome of individuals of African descent. We will use this information to develop a custom SNP chip (called the African Power Chip) to complement current, commercially available chips, and identify genetic polymorphisms associated with risk of asthma in DNA samples from 12,000 individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL104608-04
Application #
8697108
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gan, Weiniu
Project Start
2011-09-28
Project End
2015-09-29
Budget Start
2014-07-01
Budget End
2015-09-29
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sherenian, M G; Cho, S H; Levin, A et al. (2017) PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort. Clin Exp Allergy 47:1150-1158
Thakur, Neeta; Barcelo, Nicolas E; Borrell, Luisa N et al. (2017) Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies. Chest 151:804-812
Shringarpure, Suyash S; Mathias, Rasika A; Hernandez, Ryan D et al. (2017) Using genotype array data to compare multi- and single-sample variant calls and improve variant call sets from deep coverage whole-genome sequencing data. Bioinformatics 33:1147-1153
Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing et al. (2017) Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome. Sci Rep 7:46398
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Rahmani, Elior; Zaitlen, Noah; Baran, Yael et al. (2016) Sparse PCA corrects for cell type heterogeneity in epigenome-wide association studies. Nat Methods 13:443-5
Nishimura, Katherine K; Iwanaga, Kensho; Oh, Sam S et al. (2016) Early-life ozone exposure associated with asthma without sensitization in Latino children. J Allergy Clin Immunol 138:1703-1706.e1
Kessler, Michael D; Yerges-Armstrong, Laura; Taub, Margaret A et al. (2016) Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry. Nat Commun 7:12521
Abid, Z; Oh, S S; Hu, D et al. (2016) Maternal age and asthma in Latino populations. Clin Exp Allergy 46:1398-1406
Chan, Pamela Y; Carrera Silva, Eugenio A; De Kouchkovsky, Dimitri et al. (2016) The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352:99-103

Showing the most recent 10 out of 34 publications