Genetic and genomic approaches have revolutionised the way we address disease aetiology, potential treatment and methods to understand fundamental biology. Many different approaches can be applied to attempt to resolve the mechanisms through which sequence variation disrupts downstream biological processes, which I discuss and apply in this thesis. Specifically, I use tractable haematopoietic cellular systems focusing mainly on neutrophils but also extending these analyses to monocytes and naïve CD4+ cells. First, I introduce the fundamental principles of human genetic variation and associated challenges in resolving functional mechanisms. I then discuss how immune functions are dysregulated in classical autoimmune diseases and emerging evidence for the role of these cells in complex disorders not previously considered immune-mediated. I then integrate molecular phenotypes from resting monocytes, neutrophils and CD4+ T cells with disease-risk loci. Molecular data have the advantage of enabling measurement in larger cohorts and have therefore been used in quantitative trait loci studies to identify variants influencing processes such as gene expression, histone modification or splicing. Using these data, I map molecular mechanisms acting at risk loci associated with a range of complex disorders.
Following this, I highlight recent efforts in applying systematic genome-wide association approaches to cellular and functional traits, many of which can represent intermediate processes disrupted by complex disease. I then apply such approaches to novel neutrophil functional phenotypes to ascertain whether such population-based approaches can be used to gain insight into neutrophil biology. Finally, I discuss studies of haematological blood cell count traits and immunophenotyping and apply a targeted recall-by-genotype study to dissect the relationship between these traits, specifically neutrophil count and surface receptor expression.
In summary, I demonstrate how describing biological mechanisms of genetic variants requires the integration of multiple and complementary datasets and offers insight into fundamental biology, disease risk and therapeutic utility.Funding supplied by the Medical Research Council (MRC) and the Wellcome Trus
