Genome-wide Approaches to Identifying the Etiologies of Complex Diseases: Applications in Colorectal Cancer and Congenital Heart Disease.

Abstract

Complex diseases have complicated genetic architectures. A more thorough understanding of the genetic contributors to these diseases may offer new insights into the design of prevention and early intervention strategies. Combined with lower-cost, high-throughput genomic technologies, epidemiologic studies have enhanced potential to identify subgroups of the population with unique genetic etiologies and to fill in missing knowledge regarding genetic susceptibility to these complex phenotypes. This dissertation applies genome-wide association study (GWAS) approaches, as well as a whole-genome sequencing (WGS)-based co-segregation design, to identify susceptibility loci for colorectal cancer (CRC) and complex congenital heart disease (CHD). The first substantive chapter of this dissertation examines common genetic variation contributing to the etiology of CRC through a GWAS meta-analysis. This study, conducted among non-Hispanic whites and a founder population of Ashkenazi Jews from northern Israel, identified a novel, genome-wide significant risk locus for CRC on chromosome 4q32.2. The second dissertation project continues the search for CRC susceptibility loci in Ashkenazi Jews from northern Israel. This study expanded the search for microRNA (miRNA)-related polymorphisms important in the etiology of CRC across the genome and investigated the association between genetic variants in miRNA target sites and CRC risk using a novel genotyping platform. This chapter highlighted suggestive risk variants with predicted miRNA binding implications and replicated a recent association finding between an INSR variant and CRC risk. This chapter demonstrated the potential for a targeted GWAS to identify candidate risk loci and prioritize them for functional characterization. The final dissertation project identifies genetic risk factors potentially contributing to the etiology of complex CHD. The primary goal was to identify rare genetic variation underlying the development of complex CHD through WGS of a family affected by hypoplastic left heart syndrome and conotruncal defects. The hypothesis was that the clustering of anatomically distinct lesions was attributable to a more proximal defect in cardiogenesis. Ultimately, 32 variants across 29 genes were identified as causal candidates for validation, replication, and follow-up epidemiologic studies. Taken together, these dissertation chapters enhance our understanding of genetic contributors to two complex phenotypes through detailed investigation of large populations and a highly informative family.