Genetic risk converges on regulatory networks mediating early type 2 diabetes

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 Shrestha, Arushi Varshney, Lauren E. Petty, Jordan J. Wright, Christa Ventresca, Samir Agarwala, Radhika Aramandla, Greg Poffenberger, Regina Jenkins, Shaojun Mei, Nathaniel J. Hart, Sharon Phillips, Hakmook Kang, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Jie Liu, Jennifer E. Below, Stephen C. J. Parker (), Alvin C. Powers () and Marcela Brissova ()
Additional contact information
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
Jie Liu: University of Michigan
Jennifer E. Below: Vanderbilt University Medical Center
Stephen C. J. Parker: University of Michigan
Alvin C. Powers: Vanderbilt University School of Medicine
Marcela Brissova: Vanderbilt University Medical Center

Nature, 2023, vol. 624, issue 7992, 621-629

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06693-2

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