New Approaches for Empowering Studies of Asthma in Populations of African Descent

点击翻译按钮获取中文摘要

Asthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. A major goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) has been to discover genes conferring risk to asthma in populations of African ancestry. Genome-wide association studies (GWAS) have been successful in identifying genes associated with increased risk of asthma, but there is a substantial gap between associations discovered by GWAS and understanding how these loci control disease. A major portion of the `missing heritability' could be due to variants with smaller effects missed by traditional GWAS thresholds, emphasizing the need for a transition to integrative genetics, where transcriptome, proteome, methylome and metabolome information are brought into a unified framework. Our goal in this continuing renewal is to apply an integrative, multi-omics approach to understand the molecular architecture underlying asthma, building upon the 5-year CAAPA program, where >16,000 asthmatics and non-asthmatics have already been GWAS-genotyped, and GWAS and/or whole genome sequencing (WGS) data are available on more than 100,000 non-CAAPA samples. We propose to test if genetic variants control development of asthma by regulating gene transcription and expression, DNA methylation, metabolic profiles, and proteome variation. The specific aims of this application leverage an international group of investigators with diverse but highly integrated areas of expertise, and include the following: (1) expand and integrate multi-omic resources for asthma research in African Diaspora populations and identify novel genetic determinants for risk of asthma by adding indigenous American and continental African genetic representation in the African Diaspora catalog, building a multi-omic repository through newly generated transcriptome, methylome, proteome, and metabolome data from CAAPA asthmatics and unaffected controls with existing GWAS data from 7 sites in North and South America, the Caribbean and Africa, and performing integrative analyses; (2) broadly disseminate CAAPA results through a web-based resource that empowers the asthma research community for new discoveries; and (3) develop and apply approaches for prioritizing CAAPA results in 3 health systems biobanks enriched for US minority populations (Nashville, New York City, and the Rocky Mountain region) by examining genomics (PheWAS) and multi-omics (PrediXcan) asthma associations identified in CAAPA and non-CAAPA datasets. These studies will advance our understanding of the molecular basis for asthma among populations of African ancestry.