Progress in understanding type 1 diabetes through its genetic overlap with other autoimmune diseases

Abstract

Type 1 diabetes mellitus (T1DM) is the most common autoimmune disease in pediatrics with a prevalence of roughly 1 in 500 children in the USA. Genome-wide association studies have identified more than 50 variants associated with increased risk for type 1 diabetes. Comparison of these variants with those identified in other autoimmune diseases reveals three important findings: (1) there is a high degree of overlap in implicated variants in diseases with similar pathophysiology, (2) in diseases with differing pathophysiology the same variants are often implicated in opposite roles, (3) in diseases with differing pathophysiology that have many non-overlapping or oppositely implicated variants there are still several variants which are overlapping or shared. Thus, the genetic overlap between T1DM and other autoimmune diseases forms the basis for our understanding of druggable targets in type 1 diabetes.

Keywords: Autoimmunity; ENCODE; GWAS; Genomic; Type 1 diabetes mellitus.

Fig. 1

A heatmap showing the shared genetics of 15 autoimmune diseases with T1D at 34 non-MHC loci gathered from information contained at the Immunobase website (www.immunobase.org). All relevant publications can be found in a curated list at the Immunobase website. The regions are named for potential causative genes located at the locus and do not represent the actual causal gene. The regions are defined by the location of the index SNP at the locus and extending out +/–0.1 cM from that location. Yellow indicates that a SNP in this region has odds ratios that are in the same direction for both T1D and the disease in question or the direction of effect was unknown for one the diseases. Red indicates that a SNP in this region has odds ratios that are opposing each other in direction for both diseases. Orange represents a region with no known SNP sharing significance with T1D at this time. For a SNP to be considered shared it must be genome-wide significant (p<5.0×10^–8) in one of the diseases and at least suggestive of significance (p<1.0×10^{– 5}) in the other diseases. AA=alopecia areata, ATD=autoimmune thyroid disease, CEL=celiac disease, CRO=Crohn's disease, JIA=juvenile idio-pathic arthritis, MS=multiple sclerosis, PBC=primary biliary cirrhosis, PSO=psoriasis, RA=rheumatoid arthritis, SLE=systemic lupus erythematosis, T1D=type 1 diabetes, UC=ulcerative colitis, IBD=in-flammatory bowel disease, NAR=narcolepsy, PSC=primary sclerosing cholangitis, VIT=vitiligo