Genetic epidemiological and population genetic studies of complex ageing traits

The ageing process in humans is affected by lifestyle and by our genetics, the mechanisms of which we understand to varying degrees. Unpicking the phenotypic and genetic architecture of ageing traits will explain why there is such variability in the ageing phenotype. I begin with a study of physical and cognitive capability in middle to older aged individuals (Chapter 2). I use a SNP shown to associate with nicotine dependence in a Mendelian Randomization meta-analysis to explore the causality of the association of smoking with ageing, demonstrating how genetic information can be used to improve our understanding of the causal association of lifestyle and ageing traits. In Chapter 3, I meta-analyse the association of carrier status for four Mendelian diseases and physical capability, cognitive capability and lung function in ageing individuals to understand whether presumed asymptomatic heterozygotes present with a characteristic phenotype in later life. This study generated a novel finding: PI-MZ carrier status for alpha 1-antitrypsin deficiency is associated with increased height and increased respiratory capacity. In Chapter 4, I conduct the first metabochip-wide association scan of objective physical capability and self-reported disability in middle to older aged individuals, with the aim of identifying candidates for ageing genes. Lastly (Chapter 5), I conduct a simulation of evolution to test a pleiotropic model developed by Eyre-Walker (2010) regarding the genetic architecture of complex traits. I find good concordance between simulation and theory, although discrepancies arise due to the assumptions of the diffusion model. I discuss the potential portability of the pleiotropic model to the context of complex ageing traits. This thesis applies contrasting approaches to exploring phenotypic and genetic influences on complex ageing trais, enhancing our current understanding of how lifestyle and genetics shape our ageing phenome. In a world of increasing geriatric morbidity, such progress is of burgeoning importance.