RT Journal Article SR Electronic T1 Integrative cross tissue analysis of gene expression identifies novel type 2 diabetes genes JF bioRxiv FD Cold Spring Harbor Laboratory SP 108134 DO 10.1101/108134 A1 Jason M. Torres A1 Alvaro N. Barbeira A1 Rodrigo Bonazzola A1 Andrew P. Morris A1 Kaanan P. Shah A1 Heather E. Wheeler A1 Graeme I. Bell A1 Nancy J. Cox A1 Hae Kyung Im YR 2017 UL http://biorxiv.org/content/early/2017/02/27/108134.abstract AB 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.