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Meta-Analysis
. 2013 Jun;45(6):670-5.
doi: 10.1038/ng.2616. Epub 2013 Apr 21.

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Jimmy Z Liu  1 Johannes Roksund HovTrine FolseraasEva EllinghausSimon M RushbrookNadezhda T DonchevaOle A AndreassenRinse K WeersmaTobias J WeismüllerBertus EksteenPietro InvernizziGideon M HirschfieldDaniel Nils GotthardtAlbert ParesDavid EllinghausTejas ShahBrian D JuranPiotr MilkiewiczChristian RustChristoph SchrammTobias MüllerBrijesh SrivastavaGeorgios DalekosMarkus M NöthenStefan HermsJuliane WinkelmannMitja MitrovicFelix BraunCyriel Y PonsioenPeter J P CroucherMartina SterneckAndreas TeufelAndrew L MasonJanna SaarelaVirpi LeppaRuslan DorfmanDomenico AlvaroAnnarosa FloreaniSuna Onengut-GumuscuStephen S RichWesley K ThompsonAndrew J SchorkSigrid NæssIngo ThomsenGabriele MayrInke R KönigKristian HveemIsabelle CleynenJavier Gutierrez-AchuryIsis Ricaño-PonceDavid van HeelEinar BjörnssonRichard N SandfordPeter R DurieEspen MelumMorten H VatnMark S SilverbergRichard H DuerrLeonid PadyukovStephan BrandMiquel SansVito AnneseJean-Paul AchkarKirsten Muri BobergHanns-Ulrich MarschallOlivier ChazouillèresChristopher L BowlusCisca WijmengaErik SchrumpfSeverine VermeireMario AlbrechtUK-PSCSC ConsortiumJohn D RiouxGraeme AlexanderAnnika BergquistJudy ChoStefan SchreiberMichael P MannsMartti FärkkiläAnders M DaleRoger W ChapmanKonstantinos N LazaridisInternational PSC Study GroupAndre FrankeCarl A AndersonTom H KarlsenInternational IBD Genetics Consortium
Collaborators, Affiliations
Meta-Analysis

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Jimmy Z Liu et al. Nat Genet. 2013 Jun.

Abstract

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

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Figures

Figure 1
Figure 1. Association results across the nine newly associated primary sclerosing cholangitis (PSC) loci
Regional association plots of the 9 loci newly associated with PSC at genome-wide significance (P<5×10−8). Filled-in circles are directly genotyped and hollow triangles are imputed (see Online Methods) single-nucleotide polymorphisms (SNPs). The color of the marker (see legend in panel a) illustrates linkage disequilibrium with the most associated SNP. Since the most associated SNPs in panels d) and e) are located outside Immunochip fine mapping regions, association results from the discovery panel of the largest PSC genome-wide association study to date are shown as hollow circles and the most associated SNP is a hollow diamond (genotyped and imputed HapMap release 22 SNPs, cases overlap with the current study).
Figure 2
Figure 2. Genetic similarity of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) associated loci
a) Comparison of odds ratios (ORs) between the most associated risk allele in PSC and the same allele in Crohn’s disease and ulcerative colitis across the 12 genome-wide significant PSC-associated loci. Ulcerative colitis and Crohn’s disease ORs, and the denomination of IBD loci as ulcerative colitis, Crohn’s disease or both (IBD), were obtained from Jostins et al.. The error bars represent 95% confidence intervals around the ORs. *The PSC associated alleles at 6q15 (BACH2), 10p15 (IL2RA) and 19q13 (PRKD2) are independent of the reported IBD associations (r2<0.3), but locate to the same broad genetic region; for this reason these loci are defined as PSC-IBD loci in Supplementary Figure 9, but as PSC only allelic associations here. b) Predicting PSC using OR estimates across 163 IBD-associated loci. The green and orange lines represent the receiver operating characteristic (ROC) curves for discriminating PSC cases from population controls using ulcerative colitis or Crohn’s disease ORs from 163 loci associated with IBD, respectively. The dashed diagonal line is y=x, and specifies the ROC curve of a random predictor.
Figure 2
Figure 2. Genetic similarity of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) associated loci
a) Comparison of odds ratios (ORs) between the most associated risk allele in PSC and the same allele in Crohn’s disease and ulcerative colitis across the 12 genome-wide significant PSC-associated loci. Ulcerative colitis and Crohn’s disease ORs, and the denomination of IBD loci as ulcerative colitis, Crohn’s disease or both (IBD), were obtained from Jostins et al.. The error bars represent 95% confidence intervals around the ORs. *The PSC associated alleles at 6q15 (BACH2), 10p15 (IL2RA) and 19q13 (PRKD2) are independent of the reported IBD associations (r2<0.3), but locate to the same broad genetic region; for this reason these loci are defined as PSC-IBD loci in Supplementary Figure 9, but as PSC only allelic associations here. b) Predicting PSC using OR estimates across 163 IBD-associated loci. The green and orange lines represent the receiver operating characteristic (ROC) curves for discriminating PSC cases from population controls using ulcerative colitis or Crohn’s disease ORs from 163 loci associated with IBD, respectively. The dashed diagonal line is y=x, and specifies the ROC curve of a random predictor.
Figure 3
Figure 3. Pleiotropic primary sclerosing cholangitis (PSC) loci
Manhattan plot of conditional associations in PSC calculated as stratified false discovery rates (FDRs) based on the results of the present PSC analysis and genetic associations previously reported in seven immune-mediated diseases (Crohn’s disease, celiac disease, psoriasis, rheumatoid arthritis, sarcoidosis; type 1 diabetes and ulcerative colitis) (see Online Methods and Supplementary Figures 10-12). Single-nucleotide polymorphisms (SNPs) in red represent genome-wide significant findings from the regular association analysis, while SNPs listed in black are significantly associated with PSC conditional on their pleiotropic effects across the related immune-mediated diseases. The horizontal red line represents a threshold of FDR<0.001 (Supplementary Table 13), while the blue line represents a threshold of FDR<0.01 (see Supplementary Table 14 for full listing).

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