TY - JOUR
T1 - Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk Variants
AU - The Italian PBC Genetics Study Group
AU - Juran, Brian D.
AU - Hirschfield, Gideon M.
AU - Invernizzi, Pietro
AU - Atkinson, Elizabeth J.
AU - Li, Yafang
AU - Xie, Gang
AU - Kosoy, Roman
AU - Ransom, Michael
AU - Sun, Ye
AU - Bianchi, Ilaria
AU - Schlicht, Erik M.
AU - Lleo, Ana
AU - Coltescu, Catalina
AU - Bernuzzi, Francesca
AU - Podda, Mauro
AU - Lammert, Craig
AU - Shigeta, Russell
AU - Chan, Landon L.
AU - Balschun, Tobias
AU - Marconi, Maurizio
AU - Cusi, Daniele
AU - Heathcote, E. Jenny
AU - Mason, Andrew L.
AU - Myers, Robert P.
AU - Milkiewicz, Piotr
AU - Odin, Joseph A.
AU - Luketic, Velimir A.
AU - Bacon, Bruce R.
AU - Bodenheimer, Henry C.
AU - Liakina, Valentina
AU - Vincent, Catherine
AU - Levy, Cynthia
AU - Franke, Andre
AU - Gregersen, Peter K.
AU - Bossa, Fabrizio
AU - Gershwin, M. Eric
AU - Deandrade, Mariza
AU - Amos, Christopher I.
AU - Lazaridis, Konstantinos N.
AU - Seldin, Michael F.
AU - Siminovitch, Katherine A.
PY - 2012/12/1
Y1 - 2012/12/1
N2 - To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
AB - To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
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U2 - 10.1093/hmg/dds359
DO - 10.1093/hmg/dds359
M3 - Article
C2 - 22936693
VL - 21
SP - 5209
EP - 5221
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 23
ER -