@article{THESIS,
      recid = {11323},
      author = {Mu, Zepeng},
      title = {Dissecting the Genetic Basis of Human Immune-Related  Diseases},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2024-03},
      number = {THESIS},
      pages = {181},
      abstract = {In the past 15 years, genome-wide association studies  (GWAS) have identified thousands of genetic variants  associated with a plethora of human complex traits, and  greatly expanded our knowledge on their genetic  architectures. Around 90% of GWAS variants are located in  noncoding regions, suggesting that they may have regulatory  effects. However, statistical integration of GWAS and  expression quantitative trait loci (eQTL) can only explain  ~25% of GWAS variants, highlighting the challenges in  uncovering the molecular mechanisms underlying GWAS  signals. Here, we show that genetic variants affecting  pre-mRNA splicing (sQTL) can pinpoint GWAS loci missed in  eQTL. Together, eQTL and sQTL explain 40% of GWAS variants.  We demonstrate that primary, steady-state eQTL and sQTL are  largely shared among immune cell types in peripheral blood,  suggesting that it is challenging to pinpoint the exact  cell type in which these shared QTL mediate disease risk. I  also show that disease samples from the correct tissue can  capture regulatory effects distinct from healthy or in  vitro stimulated immune cells. We then investigate the  regulatory effects on chromatin accessibility and relevance  to disease. We find that chromatin accessibility (caQTL)  greatly complement eQTL/sQTL in explaining disease GWAS.  Through extensive comparisons with caQTL, eQTL and GWAS, I  conclude that partially due to enhancer pleiotropy, even  though caQTL can correctly reveal the effect of disease  variants on chromatin accessibility, it is much harder to  pinpoint the true causal gene and causal context when a  caQTL has no effect on gene expression. This highlights the  crucial importance to study more disease-relevant contexts  and integrate caQTL with multi-modal annotation data for  deeper understanding of the causal mechanisms of disease  GWAS. Taken together, our results offer a more  comprehensive understanding of the regulatory landscape of  molecular phenotypes, especially for chromatin  accessibility and gene expression, and their roles in the  genetic predisposition of immune-related diseases. We  highlight the complexity in layers of gene regulation  cascade and provide a more cautionary tale in the  interpretation of molQTL-GWAS data. We believe our work  form a basis for future studies to further extend the  boundaries of our knowledge of how genetic variants can  shape human phenotypes through regulation of a network of  molecular features.},
      url = {http://knowledge.uchicago.edu/record/11323},
      doi = {https://doi.org/10.6082/uchicago.11323},
}