Type 1 diabetes (T1D) is a complex disease involving genetic predisposition that interacts with environmental triggers, leading to the loss of insulin producing beta cells. However, the molecular cascades underlying T1D are poorly understood. We hypothesize that genetic risk factors of T1D perturb tissue-specific biological pathways and gene networks, ultimately leading 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 analysis revealed immune pathways such as adaptive immune system, cytokines and inflammatory response, primary immunodeficiency and immunoregulatory interactions between a Lymphoid and non-Lymphoid cell, across various tissues as well as tissue-specific signals such as regulation of complement cascade, class B/2 (Secretin family receptors) and neuroactive ligand-receptor interaction. Our integrative genomics approach offers comprehensive insights into the tissue-specific molecular networks and regulators underlying T1D.
M. Blencowe: None. Z. Saleem: None. X. Yang: None.
National Institutes of Health (R01DK104363)