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Genetic risk converges on regulatory networks mediating early type 2 diabetes

Author

Listed:
  • John T. Walker

    (Vanderbilt University School of Medicine)

  • Diane C. Saunders

    (Vanderbilt University Medical Center)

  • Vivek Rai

    (University of Michigan)

  • Hung-Hsin Chen

    (Vanderbilt University Medical Center)

  • Peter Orchard

    (University of Michigan)

  • Chunhua Dai

    (Vanderbilt University Medical Center)

  • Yasminye D. Pettway

    (Vanderbilt University School of Medicine)

  • Alexander L. Hopkirk

    (Vanderbilt University Medical Center)

  • Conrad V. Reihsmann

    (Vanderbilt University Medical Center)

  • Yicheng Tao

    (University of Michigan)

  • Simin Fan

    (University of Michigan)

  • Shristi Shrestha

    (Vanderbilt University Medical Center)

  • Arushi Varshney

    (University of Michigan)

  • Lauren E. Petty

    (Vanderbilt University Medical Center)

  • Jordan J. Wright

    (Vanderbilt University Medical Center)

  • Christa Ventresca

    (University of Michigan)

  • Samir Agarwala

    (University of Michigan)

  • Radhika Aramandla

    (Vanderbilt University Medical Center)

  • Greg Poffenberger

    (Vanderbilt University Medical Center)

  • Regina Jenkins

    (Vanderbilt University Medical Center)

  • Shaojun Mei

    (Vanderbilt University Medical Center)

  • Nathaniel J. Hart

    (Vanderbilt University Medical Center)

  • Sharon Phillips

    (Vanderbilt University Medical Center)

  • Hakmook Kang

    (Vanderbilt University Medical Center)

  • Dale L. Greiner

    (University of Massachusetts Medical School)

  • Leonard D. Shultz

    (The Jackson Laboratory)

  • Rita Bottino

    (Imagine Pharma
    Allegheny Health Network)

  • Jie Liu

    (University of Michigan)

  • Jennifer E. Below

    (Vanderbilt University Medical Center)

  • Stephen C. J. Parker

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Alvin C. Powers

    (Vanderbilt University School of Medicine
    Vanderbilt University Medical Center
    VA Tennessee Valley Healthcare System)

  • Marcela Brissova

    (Vanderbilt University Medical Center)

Abstract

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3–5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by β cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the β cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by β cells. RFX6 perturbation in primary human islet cells alters β cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

Suggested Citation

  • John T. Walker & Diane C. Saunders & Vivek Rai & Hung-Hsin Chen & Peter Orchard & Chunhua Dai & Yasminye D. Pettway & Alexander L. Hopkirk & Conrad V. Reihsmann & Yicheng Tao & Simin Fan & Shristi Shr, 2023. "Genetic risk converges on regulatory networks mediating early type 2 diabetes," Nature, Nature, vol. 624(7992), pages 621-629, December.
  • Handle: RePEc:nat:nature:v:624:y:2023:i:7992:d:10.1038_s41586-023-06693-2
    DOI: 10.1038/s41586-023-06693-2
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    Cited by:

    1. Andreas Müller & Nikolai Klena & Song Pang & Leticia Elizabeth Galicia Garcia & Oleksandra Topcheva & Solange Aurrecoechea Duran & Davud Sulaymankhil & Monika Seliskar & Hassan Mziaut & Eyke Schöniger, 2024. "Structure, interaction and nervous connectivity of beta cell primary cilia," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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