This project aims to investigate the genetic architecture of pectus excavatum (PE), a common congenital chest wall deformity that can affect cardiopulmonary function and quality of life. Despite evidence from family-based studies implicating collagen metabolism, cartilage development, and TGF signalling, population-level genetic data remain scarce.
Research Questions:
1. Which common and rare genetic variants are associated with susceptibility to PE?
2. What biological pathways do these variants implicate, and how might they contribute to chest wall development?
3. Are genetic risk factors for PE associated with broader clinical outcomes, including cardiopulmonary or musculoskeletal function?
Objectives:
1. Identify individuals with PE using ICD codes, imaging-derived measures, and hospital records within UK Biobank.
2. Conduct genome-wide association studies (GWAS) and integrate rare variant analyses to discover genetic variants linked to PE.
3. Explore causal relationships between identified genetic variants and clinical phenotypes using Mendelian randomization and polygenic risk scoring.
4. Assess correlations between PE genetic risk and relevant health outcomes to inform understanding of disease impact.
Scientific Rationale:
The aetiology of PE is incompletely understood, and no robust population-level genetic studies exist. By leveraging UK Biobank’s rich genomic and phenotypic datasets, this project will identify novel genetic contributors and elucidate underlying biological mechanisms. Findings will provide a foundation for improved risk prediction, early diagnosis, and potential future therapeutic strategies, contributing valuable knowledge to public health and clinical management.