RT Journal Article SR Electronic T1 Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes JF bioRxiv FD Cold Spring Harbor Laboratory SP 655670 DO 10.1101/655670 A1 Viñuela, Ana A1 Varshney, Arushi A1 van de Bunt, Martijn A1 Prasad, Rashmi B. A1 Asplund, Olof A1 Bennett, Amanda A1 Boehnke, Michael A1 Brown, Andrew A1 Erdos, Michael R. A1 Fadista, João A1 Hansson, Ola A1 Hatem, Gad A1 Howald, Cédric A1 Iyengar, Apoorva K. A1 Johnson, Paul A1 Krus, Ulrika A1 MacDonald, Patrick E. A1 Mahajan, Anubha A1 Manning Fox, Jocelyn E. A1 Narisu, Narisu A1 Nylander, Vibe A1 Orchard, Peter A1 Oskolkov, Nikolay A1 Panousis, Nikolaos I. A1 Payne, Anthony A1 Stitzel, Michael L. A1 Vadlamudi, Swarooparani A1 Welch, Ryan A1 Collins, Francis S. A1 Mohlke, Karen L. A1 Gloyn, Anna L. A1 Scott, Laura J. A1 Dermitzakis, Emmanouil T. A1 Groop, Leif A1 Parker, Stephen C.J. A1 McCarthy, Mark I. YR 2019 UL http://biorxiv.org/content/early/2019/05/31/655670.abstract AB Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.