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Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk

View ORCID ProfileJoshua Chiou, Ryan J Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Paola Benaglio, Serina Huang, Katha Korgaonkar, Sandra Heller, Alexander Kleger, Sebastian Preissl, David U Gorkin, Maike Sander, Kyle J Gaulton
doi: https://doi.org/10.1101/2021.01.13.426472
Joshua Chiou
1Biomedical Sciences Graduate Program, University of California San Diego, La Jolla CA 92093
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  • For correspondence: kgaulton@ucsd.edu joshchiou@ucsd.edu
Ryan J Geusz
1Biomedical Sciences Graduate Program, University of California San Diego, La Jolla CA 92093
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Mei-Lin Okino
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA 92093
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Jee Yun Han
3Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA 92093
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Michael Miller
3Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA 92093
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Paola Benaglio
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA 92093
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Serina Huang
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA 92093
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Katha Korgaonkar
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA 92093
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Sandra Heller
4Department of Internal Medicine I, Ulm University, Ulm, Germany
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Alexander Kleger
4Department of Internal Medicine I, Ulm University, Ulm, Germany
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Sebastian Preissl
3Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA 92093
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David U Gorkin
3Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA 92093
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Maike Sander
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA 92093
5Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla CA 92093
6Institute for Genomic Medicine, University of California San Diego, La Jolla CA 92093
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Kyle J Gaulton
2Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla CA 92093
6Institute for Genomic Medicine, University of California San Diego, La Jolla CA 92093
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  • For correspondence: kgaulton@ucsd.edu joshchiou@ucsd.edu
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ABSTRACT

Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed into 59.2M variants, which identified 74 novel association signals including several large-effect rare variants. Fine-mapping of 141 total signals substantially improved resolution of causal variant credible sets, which primarily mapped to non-coding sequence. To annotate cell type-specific regulatory mechanisms of T1D risk variants, we mapped 448,142 candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types using snATAC-seq of 131,554 nuclei. T1D risk variants were enriched in cCREs active in CD4+ T cells as well as several additional cell types including pancreatic exocrine acinar and ductal cells. High-probability T1D risk variants at multiple signals mapped to exocrine-specific cCREs including novel loci near CEL, GP2 and CFTR. At the CFTR locus, the likely causal variant rs7795896 mapped in a ductal-specific distal cCRE which regulated CFTR and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide insight into the cellular origins of complex disease.

Competing Interest Statement

KJG does consulting for Genentech and holds stock in Vertex Pharmaceuticals

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-NC-ND 4.0 International license.
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Posted January 15, 2021.
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Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk
Joshua Chiou, Ryan J Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Paola Benaglio, Serina Huang, Katha Korgaonkar, Sandra Heller, Alexander Kleger, Sebastian Preissl, David U Gorkin, Maike Sander, Kyle J Gaulton
bioRxiv 2021.01.13.426472; doi: https://doi.org/10.1101/2021.01.13.426472
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Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk
Joshua Chiou, Ryan J Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Paola Benaglio, Serina Huang, Katha Korgaonkar, Sandra Heller, Alexander Kleger, Sebastian Preissl, David U Gorkin, Maike Sander, Kyle J Gaulton
bioRxiv 2021.01.13.426472; doi: https://doi.org/10.1101/2021.01.13.426472

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