Researchers have combined two approaches—genome-wide association studies (GWAS) and single-cell epigenomics—to map the genetic underpinnings of type 1 diabetes (T1D), a condition that affects more than 1.6 million Americans. In doing so, they have made two significant contributions: 1) identified a predictive causal role for specific cell types in type 1 diabetes by supporting a role for the exocrine pancreas in the pathogenesis of T1D and 2) highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.

This work is published in Nature, in the article, “Interpreting type 1 diabetes risk with genetics and single-cell epigenomics.

“Understanding how type 1 diabetes originates at the cellular level is a critical step in finding treatments for reversing its course and, ultimately, preventing the disease altogether,” said first author Joshua Chiou, PhD, a recent graduate of the biomedical sciences graduate program at University of California, San Diego (UCSD).

T1D is a complex autoimmune disease characterized by the impairment and loss of insulin-producing pancreatic beta cells and subsequent hyperglycemia (high blood sugar), which is damaging to the body and can cause other serious health problems, such as heart disease and vision loss. T1D is less common than type 2 diabetes, but its prevalence is growing. The U.S. Centers for Disease Control and Prevention projects five million Americans will have T1D by 2050. Currently, there is no cure, only disease management.

The mechanisms of T1D, including how autoimmunity is triggered, are poorly understood. Because it has a strong genetic component, numerous GWAS have been conducted in recent years in which researchers compare whole genomes of persons with the same disease or condition, searching for differences in the genetic code that may be associated with that disease or condition.

In the case of T1D, identified at-risk variants have largely been found in the noncoding regions of the genome. In this study, researchers integrated GWAS data with epigenomic maps of cell types in peripheral blood and the pancreas.

Specifically, researchers performed the largest-to-date GWAS of T1D, analyzing 520,580 genome samples to identify 69 novel association signals. They then mapped 448,142 cis-regulatory elements (noncoding DNA sequences in or near a gene) in pancreas and peripheral blood cell types.

“By combining these two methodologies, we were able to identify cell type-specific functions of disease variants and discover a predictive causal role for pancreatic exocrine cells in type 1 diabetes, which we were able to validate experimentally,” said Kyle Gaulton, PhD, an assistant professor in the department of pediatrics at UCSD School of Medicine.

“Risk variants for T1D,” the authors wrote, “were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas.” They added: “Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression.”

“The implication is that exocrine cell dysfunction might be a major contributor to disease. This study provides a genetic roadmap from which we can determine which exocrine genes may have a role in disease pathogenesis,” noted co-author Maike Sander, MD, professor in the departments of pediatrics and cellular and molecular medicine at UCSD School of Medicine and director of the Pediatric Diabetes Research Center. Sander added that the findings represent a major leap in understanding the causes of T1D and describes the work as “a landmark study.”