Identification of Regulatory Elements and Functional Variants at GWAS Loci For Human Metabolic Traits Public Deposited

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  • March 21, 2019
  • Roman, Tamara
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • Cardiovascular disease (CVD) and type 2 diabetes (T2D) are major public health burdens in the United States. Metabolic risk factors for these diseases include increased triglyceride levels, decreased high-density lipoprotein cholesterol levels (HDL-C), and increased waist-hip ratio (WHR, a measure of body fat distribution). Genome-wide association studies (GWAS) have identified hundreds of loci for human metabolic traits and diseases. For many of these loci, the molecular and biological mechanisms are unknown. Many association signals are located in non-coding regions of the genome, and some of the associated variants are located within regulatory elements. Due to linkage disequilibrium, the GWAS identified variants may serve as proxies for the true functional variants. Functional follow-up studies are necessary to identify the functional variant(s) at a locus, determine the target gene(s) and mechanisms for how the variants and genes influence metabolic traits. I identified functional regulatory variants and elements at three GWAS loci for metabolic traits. At the GALNT2 locus for HDL-C, at least two regulatory variants demonstrated allelic differences in transcriptional enhancer activity and transcription factor binding. The alleles associated with increased HDL-C demonstrated increased GALNT2 expression in human hepatocytes and subcutaneous adipose tissue samples. At the ADCY5 locus for T2D and glucose-related traits, I identified a regulatory variant located within an enhancer element in human pancreatic islets that exhibited allelic differences in enhancer activity, differential transcription factor binding, and allelic differences in regulatory H3K27ac ChIP-seq reads from human islets. The T2D risk allele showed lower ADCY5 expression in human islets. At the PLXND1 locus for WHR, I identified at least 4 enhancer elements in human umbilical vein endothelial cells, one of which also showed enhancer activity in zebrafish endothelial cells. Functional studies helped to identify regulatory variants, elements and target genes underlying these three association signals, and provided evidence that some GWAS loci have multiple regulatory variants that act to influence gene expression. Identification of functional variants will enable the characterization of the molecular mechanisms and direction of effect in humans, leading to a greater understanding of the relationship between these variants and target genes with metabolic traits and disease.
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  • In Copyright
  • Mohlke, Karen
  • Sethupathy, Praveen
  • Maeda, Nobuyo
  • Davis, Ian
  • Rawls, John
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016

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