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.