Interpreting type 1 diabetes risk with genetics and single-cell epigenomics

Area of Science:

• Genomics and Epigenomics
• Immunology and Endocrinology

Background:

• Genome-wide association studies (GWAS) identify numerous non-coding genetic risk variants for complex diseases like type 1 diabetes (T1D).
• Understanding the functional impact of these variants requires detailed maps of gene regulation in disease-relevant cell types.

Purpose of the Study:

• To integrate large-scale GWAS data for T1D with single-cell epigenomic profiling.
• To identify candidate cis-regulatory elements (cCREs) active in pancreatic and immune cells.
• To investigate the role of exocrine pancreas in T1D pathogenesis.

Main Methods:

• Conducted a GWAS of T1D in 520,580 samples.
• Performed single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) on 131,554 nuclei from pancreas and peripheral blood mononuclear cells.
• Integrated GWAS results with snATAC-seq data to identify enriched cCREs.

Main Results:

• T1D risk variants were enriched in cCREs active in T cells and exocrine pancreatic cells (acinar and ductal).
• Several T1D risk variants overlapped with exocrine-specific cCREs linked to exocrine-specific gene expression.
• At the CFTR locus, a T1D risk variant (rs7795896) regulated CFTR expression in ductal cells, with the risk allele decreasing enhancer activity and CFTR expression.

Conclusions:

• The exocrine pancreas plays a significant role in the pathogenesis of T1D.
• Single-cell epigenomics combined with large-scale GWAS is a powerful approach to uncover the cellular origins of complex diseases.
• Specific regulatory elements in ductal cells influence T1D risk via CFTR regulation.