Large-Scale Genetic Analyses of Inflammatory Traits and Hematologic Parameters: Insights and Implications

Abstract

Genome-wide association studies (GWAS) have identified thousands of trait-associated common variants, but for most complex traits these polymorphisms have explained only a small proportion of the phenotypic variation. In an effort to assess the contribution of rare variation, sequencing based approaches targeting the exome and whole genome have now been applied to large numbers of individuals. The first aim of this dissertation seeks to identify novel associations in exome sequences from more than 9,000 participants with C-reactive protein (CRP) levels. This investigation revealed a putatively functional nonsynonymous variant in CRP and provided novel insights into variation in the apolipoprotein E gene (APOE). The second aim uses data from the exome array (primarily composed of rare variants identified through exome sequencing and a subset of common variants from GWAS) to investigate cross-phenotype associations in blood cell traits including red cell parameters (hematocrit and hemoglobin), platelet count, and white blood cell count. This analysis confirmed previously identified cross-phenotype associations and provided evidence of novel cross-phenotype associations. The final aim of this study explores the issues surrounding somatic variants as incidental findings from genetic research. This aim seeks to summarize existing recommendations related to return of incidental findings to research participants and to evaluate the case for somatic mutations as returnable incidental findings using the Janus Kinase (JAK2) p.V617F mutation as a motivating example.