PT  - JOURNAL ARTICLE
AU  - Ana Viñuela
AU  - Arushi Varshney
AU  - Martijn van de Bunt
AU  - Rashmi B. Prasad
AU  - Olof Asplund
AU  - Amanda Bennett
AU  - Michael Boehnke
AU  - Andrew Brown
AU  - Michael R. Erdos
AU  - João Fadista
AU  - Ola Hansson
AU  - Gad Hatem
AU  - Cédric Howald
AU  - Apoorva K. Iyengar
AU  - Paul Johnson
AU  - Ulrika Krus
AU  - Patrick E. MacDonald
AU  - Anubha Mahajan
AU  - Jocelyn E. Manning Fox
AU  - Narisu Narisu
AU  - Vibe Nylander
AU  - Peter Orchard
AU  - Nikolay Oskolkov
AU  - Nikolaos I. Panousis
AU  - Anthony Payne
AU  - Michael L. Stitzel
AU  - Swarooparani Vadlamudi
AU  - Ryan Welch
AU  - Francis S. Collins
AU  - Karen L. Mohlke
AU  - Anna L. Gloyn
AU  - Laura J. Scott
AU  - Emmanouil T. Dermitzakis
AU  - Leif Groop
AU  - Stephen C.J. Parker
AU  - Mark I. McCarthy
TI  - Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes
AID  - 10.1101/655670
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 655670
4099  - http://biorxiv.org/content/early/2019/05/31/655670.short
4100  - http://biorxiv.org/content/early/2019/05/31/655670.full
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.