Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects.
Wang K., Baldassano R., Zhang H., Qu H-Q., Imielinski M., Kugathasan S., Annese V., Dubinsky M., Rotter JI., Russell RK., Bradfield JP., Sleiman PMA., Glessner JT., Walters T., Hou C., Kim C., Frackelton EC., Garris M., Doran J., Romano C., Catassi C., Van Limbergen J., Guthery SL., Denson L., Piccoli D., Silverberg MS., Stanley CA., Monos D., Wilson DC., Griffiths A., Grant SFA., Satsangi J., Polychronakos C., Hakonarson H.
Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk. Additionally, we show that T1D risk alleles residing at the PTPN22, IL27, IL18RAP and IL10 loci protect against CD. Furthermore, the strongest risk alleles for T1D within the major histocompatibility complex (MHC) confer strong protection against CD and UC; however, given the multi-allelic nature of the MHC haplotypes, sequencing of the MHC locus will be required to interpret this observation. These results extend our current knowledge on genetic variants that predispose to autoimmunity, and suggest that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effect. Our analysis implies that variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations, making autoimmune diseases especially amenable to genetic dissection by genome-wide association studies.