IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-25514-6.html
   My bibliography  Save this article

Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation

Author

Listed:
  • Shubham Khetan

    (The Jackson Laboratory for Genomic Medicine
    University of Connecticut)

  • Susan Kales

    (The Jackson Laboratory for Mammalian Genetics)

  • Romy Kursawe

    (The Jackson Laboratory for Genomic Medicine)

  • Alexandria Jillette

    (The Jackson Laboratory for Genomic Medicine)

  • Jacob C. Ulirsch

    (Program in Biological and Biomedical Sciences, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Steven K. Reilly

    (Broad Institute of MIT and Harvard)

  • Duygu Ucar

    (The Jackson Laboratory for Genomic Medicine
    University of Connecticut
    Institute of Systems Genomics, University of Connecticut)

  • Ryan Tewhey

    (The Jackson Laboratory for Mammalian Genetics
    University of Maine
    Tufts University School of Medicine)

  • Michael L. Stitzel

    (The Jackson Laboratory for Genomic Medicine
    University of Connecticut
    Institute of Systems Genomics, University of Connecticut)

Abstract

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving β cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in β cell transcriptional stress response and T2D genetics.

Suggested Citation

  • Shubham Khetan & Susan Kales & Romy Kursawe & Alexandria Jillette & Jacob C. Ulirsch & Steven K. Reilly & Duygu Ucar & Ryan Tewhey & Michael L. Stitzel, 2021. "Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25514-6
    DOI: 10.1038/s41467-021-25514-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-25514-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-25514-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25514-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.