Barnes - New Approaches for Empowering Studies of Asthma in Populations of African Descent - Barbados Asthma Genetics Study (BAGS)
Epidemiologic studies of asthma have been underway in Barbados since 1991, when PI Barnes reported a relationship between modernization of the domestic environment in Barbados and increased risk of asthma. The baseline prevalence of asthma in Barbados is high (~20%), and from admixture analyses, we have determined that the proportion of African ancestry among Barbadian founders is similar to U.S. African Americans, rendering this a unique population to disentangle the genetic basis for asthma disparities among African ancestry populations in general. The primary outcome measure is asthma, and the approach for characterizing asthma in the Barbados population is based on the validated Respiratory Health Questionnaire (RHQ) designed from the 1978 American Thoracic Society questionnaire. Additional phenotype data include lung function measures, asthma severity, total serum IgE, and serum levels of various cytokines. In 1993, the Barbados Genetics of Asthma Study (BAGS) was initiated on nuclear and extended asthmatic families who self-reported as African Caribbean, resulting in the first evidence for linkage for asthma and tIgE in an African-ancestry population, and the development of novel family-based methods. Recruitment into the BAGS program was enhanced through its involvement in the international Genetics of Asthma International Network (1999-2001) and the current sample of >1300 participants continues to grow through the efforts of collaborators and nursing staff at the Chronic Disease Research Centre in Barbados. Pediatric probands were recruited through referrals at local polyclinics or the Accident and Emergency Department at the Queen Elizabeth Hospital, and their nuclear and extended family members were subsequently recruited. All subjects gave verbal and written consent as approved by the Johns Hopkins Institutional Review Board (IRB) and the Barbados Ministry of Health.
In 2007 we performed a genome-wide association study (GWAS) on 655,352 SNPs using the Illumina Infinium™ II HumanHap650Y BeadChip v.1.0 (Illumina Inc.) on a subset of 1,000 Barbados participants. This represented the first GWAS of asthma focusing exclusively on populations of African ancestry, and data from this study also contributed to the NHLBI-supported EVE Consortium. BAGS also contributed 96 samples to Phase 2 of the Thousand Genomes Project (TGP). Subsequently, BAGS samples were included in the NHLBI-supported parent grant, entitled New Approaches for Empowering Studies of Asthma in Populations of African Descent“ (R01 HL104608-01), in which whole genome sequencing (WGS) was performed on ~1,000 individuals from North, Central, and South American and Caribbean and two West African populations. These populations constitute the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA), which aims to discover genes influencing risk for asthma, and catalog genetic diversity in descendants of the African Diaspora in the Americas. So far, CAAPA sequencing has greatly expanded the lexicon of human diversity, as we have observed >20% more variants than reported in the 1000 Genome Project (TGP). Using these WGS data, a custom, gene-centric SNP genotyping array was developed by Illumina, Inc., called the African Diaspora Power Chip (ADPC), to complement current, commercially available genome-wide chips, which provide sub-optimal tagging of genes among individuals of African ancestry. This ADPC was recently genotyped on all BAGS samples, with a goal of combining ADPC data with existing GWAS data from the 650Y to test for association with asthma. The initial goals of the parent grant did not include validating the ADPC. Moreover, the ADPC, combined with existing GWAS data, will be limited in detecting contributions of rare and structural variants, which may account for some of the “missing heritability” of asthma. We therefore are performing WGS on 1,100 asthmatics and family members from the BAGS, in order to (i) expand the CAAPA WGS dataset and thereby the genomic catalog of African ancestry for the research community; (ii) validate the ADPC by capturing information from both common and rare variants; and (iii) generate additional discovery of rare and structural variants that may control risk to asthma. Tools resulting from this study will result in substantial advancements in the technology available for identifying genes relevant to disease in under-represented minorities.
Given the data available on this large, deeply genotyped cohort from a relatively homogeneous environment representing an underrepresented minority group suffering most from asthma, the BAGS sample provides a unique opportunity to employ novel genomics.