Understanding genetic determinants of obstructive respiratory diseases in cohort studies using diverse phenotypes

Chronic obstructive pulmonary disease (COPD) and asthma are major global public health concerns, particularly amongst disadvantaged socio-economic strata. Although many studies have examined cross-sectional disease and related traits, further research is needed on early disease development and disease progression to improve early detection and develop treatment strategies that are relevant across diverse populations. This thesis explores genetic and non-genetic factors which influence phenotypes related to the onset and progression of asthma and COPD in Filipino and UK populations.

I conducted a traditional observational, as well as the first genetic association study of self-reported asthma in the Cebu Longitudinal Health and Nutrition Survey (CLHNS). This provided insight into socioeconomic correlates of self-reported asthma in Filipinos, and detected a known asthma genetic variant in SMAD3 and showed that a genetic risk score was predictive of the same outcome.

I identified five signals at p<5x10-6 in a genome-wide association study (GWAS) of Preserved Ratio Impaired Spirometry (PRISm) using the Extended Cohort for E-health, Environment and DNA (EXCEED), contributing to the largest meta-GWAS of PRISM. None of the 27 SNPs from another GWAS in UK Biobank met a Bonferroni-corrected threshold (p<0.002) for replication in EXCEED. Nevertheless, I demonstrated genetic correlations between the EXCEED and UK Biobank PRISm GWAS, and between PRISm and COPD, as well as with cardiometabolic phenotypes.

Finally, a GWAS of longitudinal lung function change in UK Biobank participants with COPD highlighted the utility of electronic health records for studying COPD progression. Fourteen SNPs reached p<5x10-6, including rs34993032 near PIK3C3. PIK3C3 is involved in lung and other cancers, and the PI3K-Akt cell signalling pathway.

Overall, this thesis provides a foundational resource for future genetic studies of obstructive respiratory disease in Filipino populations, and contributes towards risk prediction, athophysiological understanding, and therapeutic target dentification for asthma and COPD-related phenotypes.