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Integrative Genomics Analysis Reveals Tissue-specific Pathways and Gene Networks for Type 1 Diabetes

  • Author(s): Blencowe, Montgomery
  • Advisor(s): Yang, Xia
  • et al.
Abstract

Type 1 diabetes (T1D) is a complex disease, involving a genetic predisposition that interacts with environmental triggers, leading to the loss of insulin producing beta cells in the pancreas. However, the molecular cascades underlying T1D are poorly understood and remain to be explored. We hypothesize that genetic risk factors of T1D perturb tissue-specific biological pathways and gene networks, which ultimately leads to the pathogenic end point in beta cells. We sought to identify the gene networks and key regulators for T1D by conducting a comprehensive, data-driven multi-omics analysis that integrates human genome-wide association studies (GWAS) of T1D, tissue-specific genetic regulation of gene expression in the form of expression quantitative trait loci (eQTLs), and tissue-specific gene network models using a computational pipeline Mergeomics. Our integrative genomics approach revealed immune pathways such as adaptive immune system, cytokines and inflammatory response, ZAP70 translocation, primary immunodeficiency and immunoregulatory interactions between a lymphoid and non-lymphoid cell, across various tissues. We also identified tissue-specific signals such as regulation of complement cascade in adipose tissue, macrophages, and monocytes, NOTCH signaling in adipose tissue and macrophages, protein folding, calcium signaling chemotaxis and lysosomal pathways in the pancreas, adipose, and monocytes, and viral infection in macrophages and monocytes. Network modelling of these pathways highlights a number of key regulator genes such as GBP1, USP18, STAT1, RPL17, HLA genes (HLA-A,-B,-C, and –G), and immunomodulatory genes (LCK, VAV1, ZAP-70), each of which has suggestive roles in the pathophysiology of T1D or other autoimmune disorders. Together, our integrative genomics approach offers comprehensive insights into the tissue-specific molecular networks and regulators as well potential between-tissue interactions underlying T1D, with potential for guiding future development of therapeutic strategies targeting the disease.

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