Multi-Ancestry Genome-wide Association Analysis and Polygenic Risk Score of Moderate-to-Severe Asthma - PROJECT SUMMARY Moderate-to-severe asthma represents 10 to 15% of all asthma cases but accounts for most of asthma-related costs and is associated with more life-threatening exacerbations than mild asthma. Environmental and genetic factors both contribute to asthma and the influence of genetics has been suggested to be as high as 70%, depending on the phenotype. Recent genome-wide association study (GWAS) evidence suggests that there are genetic variants specifically associated with moderate-to-severe asthma but not mild asthma such as the rs11603634 in MUC5AC which regulates mucin production. However, the previous GWAS were conducted exclusively in European ancestry individuals, despite non-European ancestry populations having higher risk of moderate-to-severe asthma. The goal of this project is to identify the genetic variants specifically associated with moderate-to-severe asthma compared to mild asthma in multi-ancestry and ancestry-specific GWAS and to develop and evaluate polygenic risk scores (PRS) predictive of the asthma subtype. We will use the National Institute of Health (NIH) All of Us Research Program (AoURP), an ongoing prospective cohort that has available data on 413,350 adult participants to date, of which 249,740 with array genotyping data provided access to their electronic health records. Using the Systemized Nomenclature of Medicine (SNOMED) and the 10th international classification of diseases (ICD-10) codes, we identified 6,251 moderate-to-severe asthma cases and 17,085 mild asthma controls. In moderate-to-severe asthma, the ancestries of the participants were 53.0% for European ancestry, 23.5% for African, 16.9% for Hispanic/ Latino and 6.6% for Other. Our specific aims will be 1) to determine the multi-ancestry and ancestry- specific genetic variants associated with moderate-to-severe asthma and 2) to develop and validate PRS predictive of moderate-to-severe asthma among asthmatics. In Aim 1, we will conduct the GWAS on 80% of AoURP participants with moderate-to-severe and mild asthma and perform fine mapping to identify genetic variants most likely causal. In Aim 2, we will develop and evaluate the PRS in the 20% AoURP participants remaining from Aim 1 and validate them in the UK Biobank as well as the Greater Cincinnati Pediatric Clinic Repository (GCPCR). This innovative project will be the first multi-ancestry GWAS on moderate-to-severe asthma. Upon completion, we will have determined the specific genetic variants, provided insights into the potential distinctive mechanisms and developed predictive PRS for this asthma subtype.
