A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.
Vyšlo v časopise:
A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease. PLoS Genet 7(1): e32767. doi:10.1371/journal.pgen.1001283
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001283
Souhrn
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.
Zdroje
1. BaumgartDC
CardingSR
2007 Inflammatory bowel disease: cause and immunobiology. Lancet 369 1627 1640
2. BaumgartDC
SandbornWJ
2007 Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 369 1641 1657
3. HuntKA
van HeelDA
2009 Recent advances in coeliac disease genetics. Gut 58 473 476
4. van HeelDA
WestJ
2006 Recent advances in coeliac disease. Gut 55 1037 1046
5. FestenEA
SzperlAM
WeersmaRK
WijmengaC
WapenaarMC
2009 Inflammatory bowel disease and celiac disease: overlaps in the pathology and genetics, and their potential drug targets. Endocr Metab Immune Disord Drug Targets 9 199 218
6. TursiA
GiorgettiGM
BrandimarteG
EliseiW
2005 High prevalence of celiac disease among patients affected by Crohn's disease. Inflamm Bowel Dis 11 662 666
7. DuboisPC
TrynkaG
FrankeL
HuntKA
RomanosJ
2010 Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42 295 302
8. FestenEA
GoyetteP
ScottR
AnneseV
ZhernakovaA
2009 Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 58 799 804
9. HuntKA
ZhernakovaA
TurnerG
HeapGA
FrankeL
2008 Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40 395 402
10. ParkesM
BarrettJC
PrescottNJ
TremellingM
AndersonCA
2007 Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 39 830 832
11. SmythDJ
PlagnolV
WalkerNM
CooperJD
DownesK
2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359 2767 2777
12. van HeelDA
FrankeL
HuntKA
GwilliamR
ZhernakovaA
2007 A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39 827 829
13. ZhernakovaA
FestenEM
FrankeL
TrynkaG
van DiemenCC
2008 Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am J Hum Genet 82 1202 1210
14. ChangIF
HsiaoHY
2005 Induction of RhoGAP and pathological changes characteristic of Alzheimer's disease by UAHFEMF discharge in rat brain. Curr Alzheimer Res 2 559 569
15. BarrettJC
HansoulS
NicolaeDL
ChoJH
DuerrRH
2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 955 962
16. McGovernDP
GardetA
TorkvistL
GoyetteP
EssersJ
2010 Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42 332 337
17. FestenEA
StokkersPC
van DiemenCC
van BodegravenAA
BoezenHM
2010 Genetic analysis in a Dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk. Am J Gastroenterol 105 395 402
18. WeersmaRK
StokkersPC
van BodegravenAA
van HogezandRA
VerspagetHW
2009 Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort. Gut 58 388 395
19. De JagerPL
FranchimontD
WaliszewskaA
BittonA
CohenA
2007 The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun 8 387 397
20. Tello-RuizMK
CurleyC
DelMonteT
GiallourakisC
KirbyA
2006 Haplotype-based association analysis of 56 functional candidate genes in the IBD6 locus on chromosome 19. Eur J Hum Genet 14 780 790
21. BrowningBL
BrowningSR
2009 A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 84 210 223
22. MarchiniJ
HowieB
MyersS
McVeanG
DonnellyP
2007 A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39 906 913
23. LiY
AbecasisGR
2006 MACH 1.0: Rapid haplotype reconstruction and missing genotype inference. Am J Hum Genet S79 2290
24. LinDY
SullivanPF
2009 Meta-analysis of genome-wide association studies with overlapping subjects. Am J Hum Genet 85 862 872
25. PurcellS
NealeB
Todd-BrownK
ThomasL
FerreiraMA
2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 1
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- H3K9me-Independent Gene Silencing in Fission Yeast Heterochromatin by Clr5 and Histone Deacetylases
- Rnf12—A Jack of All Trades in X Inactivation?
- Joint Genetic Analysis of Gene Expression Data with Inferred Cellular Phenotypes
- Evolutionary Conserved Regulation of HIF-1β by NF-κB