A High Resolution Capture-C Promoter "Interactome" Implicates Causal Genes at Type 2 Diabetes GWAS Loci

Abstract

GWAS has revealed many loci for type 2 diabetes (T2D). However, GWAS just reports genomic signals and not necessarily the precise localization of effector genes, with eQTLs making inferences to only a subset of such loci. Chromatin conformation capture-based techniques that detect contacts between distant regions of the genome offer an opportunity to understand GWAS signals that principally reside in non-coding regions, thus likely influencing regulatory elements. To move beyond analyzing one locus at a time and to improve on the low resolution of available Hi-C data, we developed a high resolution Capture-C based method to simultaneously characterize the genome-wide interactions of all human promoters in any cell type. We applied this to the immortalized human β-cell line, EndoC-βH1, a model relevant to T2D. We designed a custom Agilent SureSelect library targeting both ends of DpnII restriction fragments that overlap promoters of protein-coding, plus noncoding, transcripts, totaling 36,691 RNA baited fragments. Following sequencing, we investigated significant interactions at varying resolutions depending on how the fragments were leveraged and/or collapsed. In parallel, we generated ATAC-seq open chromatin maps to filter for informative proxy SNPs (r2>0.8) to each of the 104 T2D independent sentinels reported to date, yielding overall 150 (harbored in 94 DpnII fragments) for 50 of these loci. By filtering our promoter ’interactome’ results at 4 DpnII fragment resolution (median distance between interacting regions ∼115kb, median region size =1,440bp) based on these proxies and openness of the regions they interact with, we observed contacts relevant to 17 of the original loci. Some ’nearest’ genes were supported e.g., GIPR and ZFAND3, while at other loci more distant genes were implicated e.g., OGFOD2 at ’MPHOSPH9’ and MESP2 at ’AP3S2’. In conclusion, we observed informative contacts at putative effector genes for 16% of T2D GWAS loci in this particular cellular context. Disclosure E. Manduchi: None. M. Johnson: None. M. Leonard: None. S. Lu: None. K.M. Hodge: None. A. Chesi: None. A.D. Wells: None. S.F.A. Grant: None.