Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects.
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.
Wang
Kai
K
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Baldassano
Robert
R
Zhang
Haitao
H
Qu
Hui-Qi
HQ
Imielinski
Marcin
M
Kugathasan
Subra
S
Annese
Vito
V
Dubinsky
Marla
M
Rotter
Jerome I
JI
Russell
Richard K
RK
Bradfield
Jonathan P
JP
Sleiman
Patrick M A
PM
Glessner
Joseph T
JT
Walters
Thomas
T
Hou
Cuiping
C
Kim
Cecilia
C
Frackelton
Edward C
EC
Garris
Maria
M
Doran
James
J
Romano
Claudio
C
Catassi
Carlo
C
Van Limbergen
Johan
J
Guthery
Stephen L
SL
Denson
Lee
L
Piccoli
David
D
Silverberg
Mark S
MS
Stanley
Charles A
CA
Monos
Dimitri
D
Wilson
David C
DC
Griffiths
Anne
A
Grant
Struan F A
SF
Satsangi
Jack
J
Polychronakos
Constantin
C
Hakonarson
Hakon
H
D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics