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Type 1 Diabetes GWAS, Fine-Mapping Leads to New Genetic Loci, Potential Drug Targets

Insulin shot

NEW YORK – An international team led by investigators in the US and the UK has identified genetic variants, genes, and cell types with causal ties to type 1 diabetes, along with promising new drug targets.

With a genome-wide association study that included more than 61,400 individuals genotyped with an ImmunoChip array, the researchers tracked down dozens of T1D-associated loci — a set that encompassed three dozen sites with significant T1D associations that had not been reported in the past.

From there, they relied on ATAC-seq-based chromatin accessibility profiling, chromatin accessibility-related quantitative trait loci, or QTL, profiling, and other fine-mapping approaches in samples from individuals spanning multiple ancestral backgrounds to focus in on potential causal contributors to the autoimmune disease.

"We refined the set of putative causal variants and number of independent associations in many T1D regions through increased sample size, dense genotyping and imputation, inclusion of diverse ancestry groups, and optimized analytical approaches to fine mapping," co-senior authors Stephen Rich, a researcher at the University of Virginia, and John Todd, with the University of Oxford's JDRF/Wellcome Diabetes and Inflammation Laboratory, and their co-authors wrote in a study published in Nature Genetics on Monday.

Based on their analyses of new and publicly available ATAC-seq data spanning multiple cell types, the investigators saw hints that T1D risk variants may be particularly common in parts of the genome containing open chromatin regions that respond to immune stimulation in CD4+ T cells.

Based on chromatin accessibility profiles in CD4+ T cells from 48 European and 67 African individuals, for example, they found five T1D-related parts of the genome that overlapped with 11 chromatin accessibility peaks. These included five loci containing suspected causal variants for T1D. Among them was a chromosome 6 locus that included variants in and around BACH2, a gene coding for a transcriptional regulator previously implicated in adaptive immune regulation and other processes.

With additional fine-mapping analyses that incorporated chromatin interaction, expression QTL, and other data, the team narrowed in on a T1D-associated BACH2 variant known as rs72928038 that appeared to influence the expression of BACH2 itself in CD4+ T cells.

"We present a compelling hypothesis of a genetic regulatory mechanism in the T1D locus encoding the transcription factor BACH2," the authors wrote, adding that "integrating the implicated genes with immune protein networks, we identify drugs that target T1D candidate genes and networks."

Through their integrated functional genomics, protein interaction, and genetic risk variant analysis, the researchers also flagged a dozen T1D-related genes that have been targeted in clinical trials for other autoimmune conditions, though they noted that still other candidates and causal connection may emerge as genetic studies continue expanding into additional cell types and participant populations.

"Although this analysis is the largest and most comprehensive study prioritizing new gene targets in T1D according to genetic evidence, extension of future genetic studies to genome-wide analyses and continuing efforts to expand cohorts from diverse populations will further define the genetic landscape of T1D," the authors concluded.