An integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D associated genes and regulatory signals.

Genome wide association studies (GWAS) have identified over 100 signals associated with type 1 diabetes (T1D). However, translating any given T1D GWAS signal into mechanistic insights, including putative causal variants and the context (cell type and cell state) in which they function, has been limited. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in healthy and autoantibody (AAB+) human islets, as well as islets under multiple T1D stimulatory conditions. We broadly nominate effector cell types for all T1D GWAS signals. We further nominated higher-resolution contexts, including effector cell types, regulatory elements, and genes for three independent T1D risk variants acting through islet cells within the pancreas at the and loci. Subsequently, we created isogenic gene knockouts , , and , and the corresponding regulatory region knockout, , and hESCs. Loss of or , as well as knockout of the regulatory region of or increased β cell apoptosis. Additionally, pancreatic β cells derived from isogenic hESCs carrying the risk allele of exhibited increased β cell death. Finally, RNA-seq and ATAC-seq identified five genes upregulated in both and β-like cells, four of which are associated with T1D. Together, this work reports an integrative approach for combining single cell multi-omics, GWAS, and isogenic hESC-derived β-like cells to prioritize the T1D associated signals and their underlying context-specific cell types, genes, SNPs, and regulatory elements, to illuminate biological functions and molecular mechanisms.