Motivation: Twin studies estimate 50% of type 1 diabetes (T1D) risk is genetic. Genetic association has implicated T cells as central to the disease process. Thus, we generated chromatin accessibility profiles from CD4+ T cells isolated from 135 T1D cases and 144 controls and investigated whether (1) there are patterns of chromatin accessibility that differ from T1D patients compared to healthy controls; (2) established T1D risk variants influence chromatin accessibility.
Methods: Frozen PBMCs were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). CD4+ T cells were isolated using bead purification and Assay for Transposase Accessible Chromatin (ATAC-seq) was performed. ATAC-seq samples were processed using the PEPATAC pipeline and R packages edgeR and limm.
Results: We tested for differences in accessibility between individuals with and without T1D adjusting for sex, age, and experimental variability. We identified 516 chromatin regions peaks with differential accessibility by T1D status (2 with increased and 514 with decreased accessibility at FDR<0.05). Enrichment analysis with the software LOLA indicated these regions are enriched for ETS-1, AP1, and Maf transcription factor binding motifs. Next, we tested for association between T1D-associated variants and chromatin accessibility using available T1DGC genotypes. For each T1D variant with an observed chromatin accessibility quantitative trait locus effect (caQTL), we tested for colocalisation between the two signals and used publicly available expression QTLs (eQTL) to identify potential target genes. We identified six regions where data were consistent with a single variant driving association with T1D risk, chromatin accessibility in CD4+ T cells, and gene expression in whole blood, highlighting several candidate T1D genes: ANKRD55, IL6ST, BACH2, CENPW, SUOX, GDF11, GSDMB, ORMDL3, IKZF3, ERBB2, PNMT.
Conclusion: These results provide hypotheses about molecular mechanisms of T1D in CD4+ T cells.
C.C. Robertson: None. W. Chen: None. S. Onengut-Gumuscu: None. P.J. Concannon: Stock/Shareholder; Self; Amgen. Other Relationship; Self; 10x Genomics. S.S. Rich: None.
National Institute of Diabetes and Digestive and Kidney Diseases (DK111906)