University of Leicester
2022John_C_PhD.pdf (5.04 MB)

Developing and utilising longitudinal population studies to investigate genetic architecture of asthma and COPD

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posted on 2022-07-19, 10:50 authored by Catherine John

Chronic respiratory diseases, particularly asthma and COPD, cause substantial morbidity and mortality. Some individuals have features of both asthma and COPD (sometimes described as asthma-COPD overlap or ACO), and genetic risk factors for this are not fully understood. Genetic studies can identify underlying mechanisms to develop and target treatments, but require large cohorts with genotype data and phenotypic data such as self-reported diagnoses, spirometry and/or linked electronic health records (EHR). This project develops and utilises such cohorts to explore the epidemiology of asthma, COPD and ACO, and to study genetic associations with ACO.

I developed recruitment to the Extended Cohort for E-health, Environment and DNA (EXCEED), a study of over 11,000 participants, and undertook descriptive analyses to produce a cohort profile paper. I undertook epidemiological analyses of linked EHR, which demonstrated the feasibility and utility of defining ACO and acute exacerbations of COPD using this data. Alongside this, I led quality control of spirometry data in the AWI-Gen-XHALE pilot study in South Africa, contributing to establishing an additional resource for respiratory genetic epidemiology in an underserved region.

I identified eight signals reaching genome-wide significance (P<5x10-8) in a genome-wide association study of ACO. None of the signals were previously associated with ACO, and one intergenic signal on chromosome 5 was not previously associated with either asthma or COPD (rs80101740). The signals suggested a spectrum of genetic influences, some predominantly influencing asthma (signals in/near FAM105A, GLB1, PHB, TSLP), others predominantly influencing COPD (IL17RD), and others intermediate (C5orf56, HLA-DQB1). Subgroup analyses suggested that the associations were not driven by smoking or age at asthma diagnosis. I showed shared genetic influences between asthma, COPD, ACO and eosinophils at the level of individual loci and genome-wide, and highlighted pathways implicating innate and adaptive immunity and potentially bone development.



Martin Tobin; Louise Wain

Date of award


Author affiliation

Department of Health Sciences

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD



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