The effects of trait-associated variation on transcription factor binding and other regulatory phenotypes

Abstract

Understanding the genetic causes of disease is one of the fundamental goals of human genetics. Disease variants can cause dysregulation of genes, either by altering the nucleotide sequence of regulatory elements or by modifying the amino acid sequence of regulators, such as transcription factors. A widely applied strategy to search for genetic loci linked to common diseases and complex traits is genome-wide association studies (GWAS). However, genetic maps derived from GWAS implicate genomic loci with a set of correlated (i.e., virtually indistinguishable based on statistics) variants. Hence, the identities of the causal variants and causal genes are key questions that remain. In Chapters 2 and 3, I address this challenge of elucidating gene regulatory mechanisms in noncoding GWAS loci. In Chapter 2, I present a strategy of harnessing transcription factor occupancy variation data to pinpoint putative causal variants at trait-associated loci. In Chapter 3, I explore whether chromatin accessibility variation sheds light on why disease-associated gene expression variation is missing in many loci. For research of more severe diseases, such as structural birth defects, family trio studies are commonly conducted. In Chapter 4, I search for genes associated with structural birth defects by combining genetic data from multiple family trio cohorts, with the aim of identifying candidate disease variants in transcription factor genes. In sum, this dissertation discusses the challenges of pinpointing disease-causing variants and genes and presents possible strategies to address them.