Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D
Ana Viñuela, Arushi Varshney, Martijn van de Bunt, Rashmi B. Prasad, Olof Asplund, Amanda J. Bennett, Michael Boehnke, Andrew Brown, Michael R. Erdos, João Fadista, Ola Hansson, Gad Hatem, Cédric Howald, Apoorva K. Iyengar, Toby Johnson, Ulrika Krus, Patrick E. MacDonald, Anubha Mahajan, Jocelyn E. Manning Fox, Narisu Narisu, Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I. Panousis, A. J. Payne, Michael L. Stitzel, Swarooparani Vadlamudi, Ryan Welch, Francis S. Collins, Karen L. Mohlke, Anna L. Gloyn, Laura J. Scott, Emmanouil T. Dermitzakis, Leif Groop, Stephen C.J. Parker, Mark I. McCarthy
Abstract
Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.