Characterizing Cardiometabolic GWAS Loci with Regulatory Annotation, Regulatory Assays, Trans-ancestry Fine-mapping, and Open Chromatin Profiling

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  • October 10, 2018
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  • Cannon, Maren
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Cardiometabolic phenotypes, including diseases such as cardiovascular disease and type 2 diabetes (T2D) and related traits such as cholesterol levels, obesity, and lipid levels cause significant public health burden in many countries. Genetic and environmental factors contribute to the etiology of these phenotypes. While genome-wide association studies (GWAS) have identified hundreds of loci associated with cardiometabolic phenotypes, progress towards elucidating causal variants and genes has been slow. Many associated variants are located in noncoding regions, suggesting a regulatory mechanism. Identifying causal GWAS variants is a time-consuming and challenging process. Challenges arise from strong linkage disequilibrium (LD) at loci requiring multiple variants to be prioritized investigated. Combining statistical fine-mapping, overlap with genome-wide regulatory datasets, expression quantitative trait loci associations (eQTLs) and functional assays elucidates the variant(s) and gene(s) contributing to genetic mechanisms at cardiometabolic GWAS loci. I used these approaches to identify functional variants at two cardiometabolic GWAS loci and generated open chromatin profiles in adipose tissue. At the CDC123/CAMK1D T2D locus, one variant altered binding to FOXA1 and FOXA2 and increased transcriptional activity, suggesting it contributes to the mechanism at this locus. At the ANGPTL8 high-density lipoprotein cholesterol (HDL-C) GWAS locus, seven variants showed allelic differences in functional assays, suggesting a more complex regulatory mechanism that may include multiple variants. Finally, open chromatin profiles were generated from frozen human subcutaneous adipose samples and a preadipocyte strain to characterize the regulatory landscape of adipose tissue and a cellular model system used to test GWAS variants in functional assays. Thorough investigations of GWAS loci are necessary for the development of new therapies, full elucidation of direction of effect, and better understanding of the genetic contributions to cardiometabolic phenotypes.
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  • In Copyright
Advisor
  • Mack, Christopher P.
  • Mohlke, Karen
  • Davis, Ian
  • Crawford, Gregory
  • Sethupathy, Praveen
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2017
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