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Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

ABSTRACT: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS).We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing.Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients.We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.

SUBMITTER: Folseraas T

PROVIDER: S-EPMC3399030 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

Folseraas Trine T Melum Espen E Rausch Philipp P Juran Brian D BD Ellinghaus Eva E Shiryaev Alexey A Laerdahl Jon K JK Ellinghaus David D Schramm Christoph C Weismüller Tobias J TJ Gotthardt Daniel Nils DN Hov Johannes Roksund JR Clausen Ole Petter OP Weersma Rinse K RK Janse Marcel M Boberg Kirsten Muri KM Björnsson Einar E Marschall Hanns-Ulrich HU Cleynen Isabelle I Rosenstiel Philip P Holm Kristian K Teufel Andreas A Rust Christian C Gieger Christian C Wichmann H-Erich HE Bergquist Annika A Ryu Euijung E Ponsioen Cyriel Y CY Runz Heiko H Sterneck Martina M Vermeire Severine S Beuers Ulrich U Wijmenga Cisca C Schrumpf Erik E Manns Michael P MP Lazaridis Konstantinos N KN Schreiber Stefan S Baines John F JF Franke Andre A Karlsen Tom H TH

Journal of hepatology 20120418 2

<h4>Background & aims</h4>A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS).<h4>Methods</h4>We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combine ...[more]

PMID: 22521342

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Project description:Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population.Subjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) approach, using Illumina Human Omni2.5-Exome BeadChips and the following novel selection criteria for risk loci: blocks of at least 10 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium, where the distance between each adjacent SNP pair in the block was less than 30 kb, and each SNP was associated with disease at a significance level of P < 0.005. A selected index SNP from each block was validated using TaqMan SNP genotyping assays.Nineteen and twenty-one SNPs were verified as associated with PBC and PSC, respectively, by individual genotyping; 19 (10/9, PBC/PSC) SNPs reached a stringent (corrected) significance threshold and a further 21 (9/12, PBC/PSC) reached a nominal level of significance (P < 0.05 with odds ratio (OR) > 1.2 or < 0.83), providing suggestive evidence of association. The SNPs mapped to seven (1p31.3, 3q13, 6p21, 7q32.1, 11q23.3, 17q12, 19q13.33) and one (6p21) chromosome region previously associated with PBC and PSC, respectively. The SNP, rs35730843, mapping to the POLR2G gene promoter (P = 1.2 × 10-5, OR = 0.39) demonstrated the highest effect size, and was protective for PBC, whereas for PSC respective SNPs were: rs13191240 in the intron of ADGRB3 gene (P = 0.0095, OR = 0.2) and rs3822659 (P = 0.0051, OR = 0.236) along with rs9686714 (P = 0.00077, OR = 0.2), both located in the WWC1 gene.Our cost-effective GWAS approach followed by individual genotyping confirmed several previously identified associations and discovered new susceptibility loci associated with PBC and/or PSC in Polish patients. However, further functional studies are warranted to understand the roles of these newly identified variants in the development of the two disorders.

Dataset Information

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

Publications

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

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