1. Genetics and Genomics
Download icon

Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes

  1. Andrew D Skol
  2. Segun C Jung
  3. Ana Marija Sokovic
  4. Siquan Chen
  5. Sarah Fazal
  6. Olukayode Sosina
  7. Poulami P Borkar
  8. Amy Lin
  9. Maria Sverdlov
  10. Dingcai Cao
  11. Anand Swaroop
  12. Ionut Bebu
  13. DCCT/ EDIC Study group
  14. Barbara E Stranger  Is a corresponding author
  15. Michael A Grassi  Is a corresponding author
  1. Ann and Robert H Lurie Children's Hospital of Chicago,, United States
  2. NeoGenomics Laboratories, United States
  3. University Of Illinois at Chicago, United States
  4. The University of Chicago, United States
  5. Johns Hopkins University, United States
  6. National Institutes of Health, United States
  7. The George Washington University, United States
  8. Northwestern University Feinberg School of Medicine, United States
Research Article
  • Cited 0
  • Views 228
  • Annotations
Cite this article as: eLife 2020;9:e59980 doi: 10.7554/eLife.59980

Abstract

We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association to diabetic retinopathy in a genome-wide association study meta-analysis. Expression Quantitative Trait Loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified FLCN as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs to diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy. Integrating genetic association with gene expression implicated FLCN as a disease gene for diabetic retinopathy.

Article and author information

Author details

  1. Andrew D Skol

    Department of Pathology and Laboratory Medicine, Ann and Robert H Lurie Children's Hospital of Chicago,, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Segun C Jung

    Research and Development, NeoGenomics Laboratories, Aliso Viejo, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ana Marija Sokovic

    Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Siquan Chen

    Cellular Screening Center, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sarah Fazal

    Cellular Screening Center, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Olukayode Sosina

    Department of Biostatistics, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Poulami P Borkar

    Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Amy Lin

    Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Maria Sverdlov

    Research Histology and Tissue Imaging Core, University Of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Dingcai Cao

    Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Anand Swaroop

    National Eye Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1975-1141
  12. Ionut Bebu

    Biostatistics Center, The George Washington University, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. DCCT/ EDIC Study group

  14. Barbara E Stranger

    Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
    For correspondence
    barbara.stranger@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
  15. Michael A Grassi

    Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
    For correspondence
    grassim@uic.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8467-3223

Funding

National Eye Institute (R01EY023644)

  • Michael A Grassi

National Eye Institute (ZIAEY000546)

  • Anand Swaroop

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. David E James, The University of Sydney, Australia

Publication history

  1. Received: June 13, 2020
  2. Accepted: November 6, 2020
  3. Accepted Manuscript published: November 9, 2020 (version 1)

Copyright

? 2020, Skol et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 228
    Page views
  • 37
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Evolutionary Biology
    2. Genetics and Genomics
    Richard Benton et al.
    Short Report

    The insect chemosensory repertoires of Odorant Receptors (ORs) and Gustatory Receptors (GRs) together represent one of the largest families of ligand-gated ion channels. Previous analyses have identified homologous 'Gustatory Receptor-Like (GRL)' proteins across Animalia, but the evolutionary origin of this novel class of ion channels is unknown. We describe a survey of unicellular eukaryotic genomes for GRLs, identifying several candidates in fungi, protists and algae that contain many structural features characteristic of animal GRLs. The existence of these proteins in unicellular eukaryotes, together with ab initio protein structure predictions, provide evidence for homology between GRLs and a family of uncharacterized plant proteins containing the DUF3537 domain. Together, our analyses suggest an origin of this protein superfamily in the last common eukaryotic ancestor.

    1. Evolutionary Biology
    2. Genetics and Genomics
    Fan Han et al.
    Research Article

    Atlantic herring is widespread in North Atlantic and adjacent waters and is one of the most abundant vertebrates on earth. This species is well suited to explore genetic adaptation due to minute genetic differentiation at selectively neutral loci. Here we report hundreds of loci underlying ecological adaptation to different geographic areas and spawning conditions. Four of these represent megabase inversions confirmed by long read sequencing. The genetic architecture underlying ecological adaptation in herring deviates from expectation under a classical infinitesimal model for complex traits because of large shifts in allele frequencies at hundreds of loci under selection.