| Application: | 19136, Lung Health: Genes and environment |
| Title: | Lung Development Genes and Adult Lung Function |
| Size: | 557812 B |
| Archived: | 30 Jun 2021 |
| Stability: | Complete |
| Personal: | No individual-level data |
Return 3610
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Notes
Epidemiological evidence suggests that poor lung function and lung disease in adult life may occur partly through suboptimal growth and development. We systematically investigated the effects of lung development genes on adult lung function.Using data from UK Biobank, we tested the association of 391 genes known to influence lung development based on animal and human evidence, with FVC and FEV1/FVC. We split the available dataset into two random subsets of 207,616 and 138,411 individuals, using the larger to select the most promising signals and the smaller for replication.
Overall, we identified 55 lung development related genes associated with adult lung function; of which 36 are novel (16 for FVC; 19 for FEV1/FVC; 1 for both), showing the value of our hypothesis-driven approach in complementing agnostic GWAS. Most of these 36 signals were intronic variants and expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 at nominal significance level. 53 of the 55 genes fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-cell adhesion; extra-cellular matrix), suggesting that these specific processes are important for adult lung health.
Our study demonstrates the role of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns; their further investigation might lead to druggable targets.
Application 19136
Lung Health: Genes and environment
Lung function is an important marker of overall health. Poor lung function is associated with respiratory disability, poor quality of life and overall mortality. Individuals that experience an excessive decline in lung function with ageing, develop clinical symptoms of respiratory disability, impaired ventilatory function and, ultimately, chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. This proposal aims to improve our knowledge of the genetic, environmental and lifestyle determinants of lung function and to further understand what drives its decline with age. The proposed research will contribute to further the understanding of the factors associated with lung function and to improve the prediction of lung function decline with ageing. It fits UK Biobank?s stated purpose as it will help elucidate pathophysiological mechanisms of lung disease and contribute to the prevention, risk stratification and treatment of diseases such as COPD. Our goal is to use the UK Biobank data to assess genetic and environmental risk factors associated with lung function. We will: 1) apply new statistical approaches to the analysis of genetic data in order to find novel variants associated with lung function; 2) perform association studies of genes in candidate pathways and gene-environment interactions that influence lung function; and 3) perform Mendelian randomization studies to investigate causal effects of modifiable risk factors for lung function and lung disease (e.g. asthma and COPD), using genes as instrumental variables. We request access to the entire cohort, including follow-ups, and to all currently available genotype data. The data from the entire cohort will be used for the purpose of conducting epidemiological analyses investigating genetic and non-genetic factors associated with lung function and disease.
| Lead investigator: | Dr Deborah Jarvis |
| Lead institution: | Imperial College London |
1 related Return
| Return ID | App ID | Description | Archive Date |
|---|---|---|---|
| 2578 | 19136 | Age at menopause and lung function: a Mendelian Randomization study | 27 Oct 2020 |
1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 3611 | Lung Development Genes and Adult Lung Function | Portas L et al. | 2020 | Am J Respir Crit Care Med |
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