Improving representation of African-ancestry populations in genetic association studies of lung function traits

Lung function is a key predictor of morbidity and mortality from diseases used in diagnosing and grading severity of chronic obstructive pulmonary disease (COPD). While genome-wide association studies (GWAS) have identified 1,020 loci associated with spirometric traits, these findings are based on largely European-ancestry populations. African-ancestry populations remain vastly underrepresented in GWAS, hindering equitable application of, and benefits from genomic medicine. This PhD investigates both genetic and non-genetic determinants of lung function in African populations, using data from the Africa Wits-INDEPTH Partnership for Genomic Studies (AWI-Gen) and other African-ancestry cohorts.Chapter 2 presents the generation of curated, high-quality spirometry phenotypes for 1,767 AWI-Gen participants, followed by a study of non-genetic predictors of lung function in the AWI-Gen population. Chapter 3 reports the first genome-wide association study of lung function traits conducted exclusively in individuals recruited from the African continent, and demonstrates the use of these data to calibrate polygenic risk scores for lung function in African populations. Chapter 4 delivers the largest GWAS meta-analysis of lung function in African-ancestry populations to date (N = 10,356), while Chapter 5 applies multiple variant-to-gene mapping approaches to describe biologically plausible effector genes for lung function.I identified 130 lung function sentinels at GWAS P