Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers

Abstract

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.

Fig. 1

T1D ImmunoChip p-value enrichment analysis. Panel (a) shows Z scores for densely typed regions against diseases curated in ImmunoBase. Diseases with positive Z scores indicate evidence for overall genetic overlap with T1D, within densely typed regions accessible on ImmunoChip. Those with negative scores indicate evidence for negative association. Each bar is labelled with the Wilcoxon rank sum test p-value and coloured by disease autoantibody positive/negative status. The MHC region (chr6:25Mb..35Mb GRCh37) was excluded from analysis. AA- Alopecia Areata, AS - Ankylosing Spondylitis ATD - Autoimmune thyroid disease,, CEL- Celiac disease, CD - Crohn’s disease, JIA - Juvenile Idiopathic Arthritis, MS - Multiple Sclerosis, NAR – Narcolepsy, PBC - Primary Biliary Cirrhosis, PSC- Primary Sclerosing Cholangitis PSO - Psoriasis, RA - Rheumatoid Arthritis, SJO – Sjogren’s syndrome, SLE Systemic Lupus Erythematosus, UC - Ulcerative Colitis. Panels (b) and (c) show P′ = min(−log(p.t1d.meta)) for each densely typed region accessible on the ImmunoChip excluding the MHC and autosomal regions. Regions that overlap known T1D susceptibility regions are identified by blue bars, whereas yellow and pink show JIA and UC overlap respectively (http://www.ImmunoBase.org – accessed February 13, 2014). Red bars denote shared overlap between T1D and focal disease. The y-axis is truncated for clarity. A fully interactive version of panels (b) and (c), along with further supporting resources are available at http://www.immunobase.org/poster/type-1-diabetes-immunochip-study-onengut-gumuscu/.

Fig. 2

Heat map showing chromatin state enrichment analysis of T1D 99% credible SNP set in ImmunoChip densely mapped regions versus the complement set, within Epigenomic Roadmap and ENCODE tissues. The top coloured row groups cell-types into 4 anatomical categories with relevance to type 1 diabetes, subsequent rows use a red (enrichment) to blue (depletion) scale to illustrate enrichment in a particular chromatin state (1_TssA – Active Tss, 2_TssAFlnk – Flanking Active TSS, 3_TxFlnk – Transcribed at gene 5′ and 3′, 4_Tx – Strong transcription, 5_TxWk – Weak transcription, 6_EnhG – Genic Enhancer, 7_Enh - Enhancer, 8_ZNF/Rpts – ZNF genes & repeats, 9_Het - Heterochromatin, 10_TssBiv- Bivalent/Poised TSS, 11_BivFlnk – Flanking Bivalent TSS/Enhancer, 12_EnhBiv – Bivalent enhancer, 13_RepPC – Repressed PolyComb, 14_RepPCWk – Weak repressed polycomb, 15_Quies – Quiescent/Low).