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Integrative cross tissue analysis of gene expression identifies novel type 2 diabetes genes

Jason M. Torres, Alvaro N. Barbeira, Rodrigo Bonazzola, Andrew P. Morris, Kaanan P. Shah, Heather E. Wheeler, Graeme I. Bell, Nancy J. Cox, View ORCID ProfileHae Kyung Im
doi: https://doi.org/10.1101/108134
Jason M. Torres
1Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, The University of Chicago, Chicago, IL, USA
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Alvaro N. Barbeira
2Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Rodrigo Bonazzola
2Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Andrew P. Morris
3Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Kaanan P. Shah
2Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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Heather E. Wheeler
4Departments of Biology and Computer Science, Loyola University Chicago, Chicago, IL, USA
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Graeme I. Bell
5Department of Medicine, The University of Chicago, Chicago, IL, USA
6Department of Human Genetics, The University of Chicago, Chicago, IL, USA
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Nancy J. Cox
7Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA
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  • For correspondence: nancy.j.cox@vanderbilt.edu haky@uchicago.edu
Hae Kyung Im
2Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
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  • ORCID record for Hae Kyung Im
  • For correspondence: nancy.j.cox@vanderbilt.edu haky@uchicago.edu
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Abstract

To understand the mechanistic underpinnings of type 2 diabetes (T2D) loci mapped through GWAS, we performed a tissue-specific gene association study in a cohort of over 100K individuals (ncases ≈ 26K, ncontrols ≈ 84K) across 44 human tissues using MetaXcan, a summary statistics extension of PrediXcan. We found that 90 genes significantly (FDR < 0.05) associated with T2D, of which 24 are previously reported T2D genes, 29 are novel in established T2D loci, and 37 are novel genes in novel loci. Of these, 13 reported genes, 15 novel genes in known loci, and 6 genes in novel loci replicated (FDRrep < 0.05) in an independent study (ncases ≈ 10K, ncontrols ≈ 62K). We also found enrichment of significant associations in expected tissues such as liver, pancreas, adipose, and muscle but also in tibial nerve, fibroblasts, and breast. Finally, we found that monogenic diabetes genes are enriched in T2D genes from our analysis suggesting that moderate alterations in monogenic (severe) diabetes genes may promote milder and later onset type 2 diabetes.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 27, 2017.
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Integrative cross tissue analysis of gene expression identifies novel type 2 diabetes genes
Jason M. Torres, Alvaro N. Barbeira, Rodrigo Bonazzola, Andrew P. Morris, Kaanan P. Shah, Heather E. Wheeler, Graeme I. Bell, Nancy J. Cox, Hae Kyung Im
bioRxiv 108134; doi: https://doi.org/10.1101/108134
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Integrative cross tissue analysis of gene expression identifies novel type 2 diabetes genes
Jason M. Torres, Alvaro N. Barbeira, Rodrigo Bonazzola, Andrew P. Morris, Kaanan P. Shah, Heather E. Wheeler, Graeme I. Bell, Nancy J. Cox, Hae Kyung Im
bioRxiv 108134; doi: https://doi.org/10.1101/108134

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