135-OR: Mapping Cis-Regulatory Programs Affecting Diabetes Risk in Pancreatic Islet Cell Types Using Single-Cell Multimodal Profiling

Abstract

Genetic variants influencing type 1 diabetes (T1D) risk identified by genome-wide association studies (GWAS) are primarily non-coding and affect cis-regulatory element (cRE) activity in specific cell types. A more detailed understanding of cell type-specific cis-regulatory programs in the pancreas is therefore crucial for deciphering the functional impact of T1D risk. Recently developed assays that generate multimodal single nucleus RNA-seq (snRNA-seq) and ATAC-seq (snATAC-seq) profiles from the same cell enable high-resolution mapping of cis-regulatory programs in specific cell types. We generated deeply sequenced data from 28 nondiabetic pancreatic islet samples from the Alberta Diabetes Institute IsletCore using 10x multiome assays. After extensive quality control and filtering, we clustered multimodal profiles from 174,819 cells and identified ten major cell types. For several cell types we identified evidence of heterogeneous sub-populations; for example, in beta cells there were six sub-populations corresponding to cellular states associated with insulin secretion, stress response, and others. We identified 263,223 cREs across all cell types and developed a novel method to predict target genes of cREs based on the correlation of multimodal profiles across single cells. In beta cells, there were 122,352 cRE-target gene links involving 16,907 unique genes. We mapped chromatin accessibility quantitative trait loci (caQTLs) for cREs in each cell type and identified a total of 14,535 caQTLs at FDR<.10. Finally, we annotated T1D risk variants from high-resolution fine-mapping of 136 T1D signals with cRE-target gene links and caQTLs. At 27 T1D signals including at the INS, MAPT, and DLK1 loci, variants affecting chromatin accessibility were linked to putative target genes in beta cells suggesting mechanisms of action at these loci. Experimental follow up of variant activity at these loci using genome editing in beta cell lines is ongoing. Disclosure H. Mummey: None. W. Elison: None. K. Korgaonkar: None. Y.S. Lee: None. J.M. Newsome Ashmus: None. P. Benaglio: Employee; Shoreline Biosciences. M.T. Miller: None. J.E. Manning Fox: None. A.L. Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. P. MacDonald: None. S. Preissl: None. K.J. Gaulton: Stock/Shareholder; Neurocrine Biosciences, Inc. Consultant; Genentech, Inc. Stock/Shareholder; Vertex Pharmaceuticals Incorporated. Funding National Institutes of Health (HG012059, DK105554, DK122607, DK114650)