@article{Regulation:2746,
      recid = {2746},
      author = {Joslin, Amelia Christine},
      title = {Insights Into Gene Regulation and Disease at Obesity GWAS  Loci},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2020-12},
      pages = {125},
      abstract = {While genome-wide association studies (GWAS) have  identified variants and genes associated with human  disease, a comprehensive understanding of the genetic  architecture of individual loci and the functional  implications of these associations remains incomplete. In  this work, we applied an integrated pipeline to chart the  regulatory landscapes of obesity-associated loci within two  cell types central to obesity etiology. In both adipocytes  and hypothalamic neurons, we annotated gene expression,  chromatin accessibility, and long-range chromatin  interactions across multiple differentiation stages.  Additionally, we generated a list of 2,396 variants in high  LD with BMI lead SNPs and tested them in a massively  parallel reporter assay to identify putatively causal  variants modulating enhancer activity. We identified 94  variants within enhancers that displayed  enhancer-modulating properties, many of which were active  in both cell types. Our data show that individual GWAS loci  harbor multiple candidate causal variants within distinct  enhancers that display cross-tissue effects. Integrating  the identified enhancer modulating variants (EMVars) with  chromatin interactions and eQTL information generated a  comprehensive list of genes predicted to underlie obesity  GWAS associations. Aggregating our data across multiple  time points allowed us to assign more candidate causal  variants to genes compared to regulatory maps in a single  cell type and to prioritize 232 genes with varying degrees  of evidence for obesity risk importance. We used these  insights during experimental dissection of a complex  genomic interval on 16p11.2 where we observed EMVars at two  independent GWAS loci exhibiting megabase-range,  cross-locus Hi-C chromatin interactions and shared eQTL  effects. We provide evidence that EMVars within these two  loci converge to regulate a shared gene set. Together, our  data chart the genetic architecture of obesity-associated  loci and support a model in which many GWAS loci contain  multiple variants that impair the activities of distinct  enhancers across tissues, potentially with temporally  restricted effects, to impact the expression of multiple  genes. This complex network model has broad implications  for ongoing variant to function efforts to mechanistically  dissect GWAS.},
      url = {http://knowledge.uchicago.edu/record/2746},
      doi = {https://doi.org/10.6082/uchicago.2746},
}