Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes

View ORCID ProfileAna Viñuela, View ORCID ProfileArushi Varshney, View ORCID ProfileMartijn van de Bunt, View ORCID ProfileRashmi B. Prasad, Olof Asplund, Amanda Bennett, View ORCID ProfileMichael Boehnke, View ORCID ProfileAndrew Brown, View ORCID ProfileMichael R. Erdos, João Fadista, View ORCID ProfileOla Hansson, Gad Hatem, Cédric Howald, Apoorva K. Iyengar, Paul Johnson, Ulrika Krus, View ORCID ProfilePatrick E. MacDonald, View ORCID ProfileAnubha Mahajan, Jocelyn E. Manning Fox, View ORCID ProfileNarisu Narisu, View ORCID ProfileVibe Nylander, View ORCID ProfilePeter Orchard, Nikolay Oskolkov, View ORCID ProfileNikolaos I. Panousis, Anthony Payne, View ORCID ProfileMichael L. Stitzel, Swarooparani Vadlamudi, View ORCID ProfileRyan Welch, View ORCID ProfileFrancis S. Collins, View ORCID ProfileKaren L. Mohlke, View ORCID ProfileAnna L. Gloyn, View ORCID ProfileLaura J. Scott, View ORCID ProfileEmmanouil T. Dermitzakis, Leif Groop, View ORCID ProfileStephen C.J. Parker, View ORCID ProfileMark I. McCarthy
doi: https://doi.org/10.1101/655670
Ana Viñuela
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ana Viñuela
  • For correspondence: mark.mccarthy@drl.ox.ac.uk ana.vinuela@unige.ch
Arushi Varshney
4Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Arushi Varshney
Martijn van de Bunt
5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
6Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK
7Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, OX3 7LE, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Martijn van de Bunt
Rashmi B. Prasad
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Rashmi B. Prasad
Olof Asplund
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amanda Bennett
5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Boehnke
9Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michael Boehnke
Andrew Brown
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andrew Brown
Michael R. Erdos
10Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michael R. Erdos
João Fadista
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
12Department of Genetics, University of North Carolina, Chapel Hill, NC 27599
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ola Hansson
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ola Hansson
Gad Hatem
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cédric Howald
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Apoorva K. Iyengar
12Department of Genetics, University of North Carolina, Chapel Hill, NC 27599
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Johnson
5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ulrika Krus
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patrick E. MacDonald
13Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Patrick E. MacDonald
Anubha Mahajan
5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Anubha Mahajan
Jocelyn E. Manning Fox
13Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Narisu Narisu
10Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Narisu Narisu
Vibe Nylander
6Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Vibe Nylander
Peter Orchard
14Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Peter Orchard
Nikolay Oskolkov
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nikolaos I. Panousis
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nikolaos I. Panousis
Anthony Payne
5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael L. Stitzel
15The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032
16Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut, Farmington, CT 06032
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michael L. Stitzel
Swarooparani Vadlamudi
12Department of Genetics, University of North Carolina, Chapel Hill, NC 27599
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ryan Welch
9Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ryan Welch
Francis S. Collins
10Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Francis S. Collins
Karen L. Mohlke
12Department of Genetics, University of North Carolina, Chapel Hill, NC 27599
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Karen L. Mohlke
Anna L. Gloyn
5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
6Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK
7Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, OX3 7LE, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Anna L. Gloyn
Laura J. Scott
9Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Laura J. Scott
Emmanouil T. Dermitzakis
1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
2Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland
3Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Emmanouil T. Dermitzakis
Leif Groop
8Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
17Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen C.J. Parker
4Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109
14Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stephen C.J. Parker
Mark I. McCarthy
5Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
6Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK
7Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, OX3 7LE, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mark I. McCarthy
  • For correspondence: mark.mccarthy@drl.ox.ac.uk ana.vinuela@unige.ch
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted May 31, 2019.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes
Ana Viñuela, Arushi Varshney, Martijn van de Bunt, Rashmi B. Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew 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, Mark I. McCarthy
bioRxiv 655670; doi: https://doi.org/10.1101/655670
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Influence of genetic variants on gene expression in human pancreatic islets – implications for type 2 diabetes
Ana Viñuela, Arushi Varshney, Martijn van de Bunt, Rashmi B. Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew 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, Mark I. McCarthy
bioRxiv 655670; doi: https://doi.org/10.1101/655670

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3586)
  • Biochemistry (7545)
  • Bioengineering (5495)
  • Bioinformatics (20732)
  • Biophysics (10294)
  • Cancer Biology (7951)
  • Cell Biology (11611)
  • Clinical Trials (138)
  • Developmental Biology (6586)
  • Ecology (10168)
  • Epidemiology (2065)
  • Evolutionary Biology (13580)
  • Genetics (9521)
  • Genomics (12817)
  • Immunology (7906)
  • Microbiology (19503)
  • Molecular Biology (7641)
  • Neuroscience (41982)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2192)
  • Physiology (3259)
  • Plant Biology (7025)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1947)
  • Systems Biology (5419)
  • Zoology (1113)