Biology subjects

HPAP Consortium,

Publications and source records attributed to HPAP Consortium,.

4 recordsLinked to original sources

bioRxiv2026

Utilizing single-cell data for per-cell type eQTL mapping in the human pancreas

Aims/hypothesis The human pancreas is a central organ for metabolic regulation that is comprised of diverse cell types that uniquely contribute to its function. Previous studies have performed expression quantitative trail loci (eQTL) discovery in either whole pancreas or in pancreatic islets, but due to differences between pancreatic cell types, this approach does not reveal cell type-specific effects. In this study, we sought to either implicate the cell type of action for known eQTLs or identify new eQTLs that may have been masked in bulk studies by performing eQTL discovery in individual pancreatic cell types. Methods We clustered 153,018 single-cell RNA sequencing (scRNA-seq) data from 71 pancreatic islet donors from the Human Pancreas Analysis Program (HPAP). We performed eQTL discovery in six pancreatic cell types using this resource directly. We further utilized this single cell resource as a reference to deconvolute bulk pancreatic RNA sequencing data from 305 Genotype Tissue Expression (GTEx) project donors and performed eQTL discovery in four pancreatic cell types. Finally, we performed fine-mapping and co-localization of pancreatic cell type eQTLs with metabolic GWAS to connect our findings to metabolic disease risk. Results From analyzing 71 individuals with single cell profiles, we identified 112 unique eGenes across six pancreatic cell types, 99 of which had been identified previously and 13 unique to this study. From the deconvoluted eQTLs, we identified 3,134 unique eGenes across four pancreatic cell types, 116 of which were unique to our study. Fine-mapping and co-localization of eQTLs with metabolic GWAS yielded key leads that warrant further investigation, such as the association of rs2168101 with LMO1 expression in alpha cells. Conclusions/interpretation We identified new signals that were previously not found in bulk pancreatic eQTL studies and potential cell type of action for several signals that were identified previously. Although there are limitations to the power, and therefore, discoverability of this study, it provides insights into how individual pancreatic cells differently contribute to metabolic disease.

genetics↗

bioRxiv2024

Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset

Autoimmune destruction of pancreatic {beta} cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, {beta} cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.

immunology↗

bioRxiv2022

Single-cell gene expression and chromatin accessibility profiling of human pancreatic islets at basal and stimulatory conditions nominates mechanisms of type 1 diabetes genetic risk

Type 1 diabetes (T1D) is a complex autoimmune disease characterized by the loss of pancreatic islet beta cells. The mechanisms of T1D genetic risk remain poorly understood. Here, we present a multi-omic integrative study of single-cell/nucleus molecular profiles of gene expression and chromatin accessibility in the same biological samples from healthy and beta cell autoantibody+ (AAB+) human pancreatic islets to characterize mechanisms of islet-mediated T1D genetic risk. We additionally performed single-cell/nucleus multi-omic profiling of healthy islets under two stimulatory conditions used as in vitro models of T1D (cytokine cocktail and CVB4 infection) to evaluate how environmental exposures recapitulate multi-omic signatures of T1D. In total, we analyzed 121,272 cells/nuclei across 34 libraries, identifying 10 distinct cell types. We identified cell-type-specific and disease-associated cis-regulatory elements and nominated likely target genes. We provide evidence that T1D genetic risk is mediated through multiple pancreatic cell populations, including islet endocrine cells (beta, alpha, gamma, and delta), exocrine acinar and ductal cells, and immune cells. Finally, we identified three independent T1D risk variants acting through pancreatic islet endocrine cells at the TOX, RASGRP1, and DLK1/MEG3 loci. Together, this work improves our understanding of how non-coding genetic variants encode T1D risk through a complex interplay of different cell types in the pancreas.

genomics↗

bioRxiv2021

Multiomics single-cell analysis of human pancreatic islets reveals novel cellular states in health and type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease of only partially defined etiology in which immune cells destroy insulin-producing beta cells. Using single-cell transcriptomics and an advanced analytical strategy to assess pancreatic islets of T1D, autoantibody-positive, and non-diabetic organ donors, we identified both canonical cell types and rare insulin-expressing cells with a hybrid mixture of endocrine and exocrine gene signatures within all donors. We further found elevated expression of MHC Class II pathway genes in exocrine ductal cells of T1D donors, which we confirmed through CyTOF, in situ imaging mass cytometry, and immunofluorescence analysis. Taken together, our multimodal analyses identify novel cell types and processes that may contribute to T1D immunopathogenesis and provide new cellular and molecular insights into human pancreas function.

genomics↗