Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

Ana Viñuela (), Arushi Varshney, Martijn Bunt, Rashmi B. Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew A. Brown, Michael R. Erdos, João Fadista, Ola Hansson, Gad Hatem, Cédric Howald, Apoorva K. Iyengar, Paul Johnson, Ulrika Krus, Patrick E. MacDonald, Anubha Mahajan, Jocelyn E. Manning Fox, Narisu Narisu, Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I. Panousis, Anthony 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 and Mark I. McCarthy ()
Additional contact information
Ana Viñuela: University of Geneva Medical School
Arushi Varshney: University of Michigan
Martijn Bunt: University of Oxford
Rashmi B. Prasad: Lund University, Skåne University Hospital
Olof Asplund: Lund University, Skåne University Hospital
Amanda Bennett: University of Oxford
Michael Boehnke: University of Michigan
Andrew A. Brown: University of Geneva Medical School
Michael R. Erdos: National Human Genome Research Institute, National Institutes of Health
João Fadista: Lund University, Skåne University Hospital
Ola Hansson: Lund University, Skåne University Hospital
Gad Hatem: Lund University, Skåne University Hospital
Cédric Howald: University of Geneva Medical School
Apoorva K. Iyengar: University of North Carolina
Paul Johnson: University of Oxford
Ulrika Krus: Lund University, Skåne University Hospital
Patrick E. MacDonald: University of Alberta
Anubha Mahajan: University of Oxford
Jocelyn E. Manning Fox: University of Alberta
Narisu Narisu: National Human Genome Research Institute, National Institutes of Health
Vibe Nylander: University of Oxford
Peter Orchard: Department of Computational Medicine & Bioinformatics, University of Michigan
Nikolay Oskolkov: Lund University, Skåne University Hospital
Nikolaos I. Panousis: University of Geneva Medical School
Anthony Payne: University of Oxford
Michael L. Stitzel: The Jackson Laboratory for Genomic Medicine
Swarooparani Vadlamudi: University of North Carolina
Ryan Welch: University of Michigan
Francis S. Collins: National Human Genome Research Institute, National Institutes of Health
Karen L. Mohlke: University of North Carolina
Anna L. Gloyn: University of Oxford
Laura J. Scott: University of Michigan
Emmanouil T. Dermitzakis: University of Geneva Medical School
Leif Groop: Lund University, Skåne University Hospital
Stephen C. J. Parker: University of Michigan
Mark I. McCarthy: University of Oxford

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18581-8

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