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

Brian D. Juran, Gideon M. Hirschfield, Pietro Invernizzi, Elizabeth J. Atkinson, Yafang Li, Gang Xie, Roman Kosoy, Michael Ransom, Ye Sun, Ilaria Bianchi, Erik M. Schlicht, Ana Lleo, Catalina Coltescu, Francesca Bernuzzi, Mauro Podda, Craig Lammert, Russell Shigeta, Landon L. Chan, Tobias Balschun, Maurizio MarconiDaniele Cusi, E. Jenny Heathcote, Andrew L. Mason, Robert P. Myers, Piotr Milkiewicz, Joseph A. Odin, Velimir A. Luketic, Bruce R. Bacon, Henry C. Bodenheimer, Valentina Liakina, Catherine Vincent, Cynthia Levy, Andre Franke, Peter K. Gregersen, Fabrizio Bossa, M. Eric Gershwin, Mariza De Andrade, Christopher I. Amos, Konstantinos N. Lazaridis, Michael F. Seldin, Katherine A. Siminovitch

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numberdds359
Pages (from-to)5209-5221
Number of pages13
JournalHuman Molecular Genetics
Volume21
Issue number23
DOIs
StatePublished - Dec 1 2012

Fingerprint

Biliary Liver Cirrhosis
Haplotypes
Single Nucleotide Polymorphism
Alleles
Genotype
Genes
Autoimmune Diseases
Meta-Analysis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

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. / Juran, Brian D.; Hirschfield, Gideon M.; Invernizzi, Pietro; Atkinson, Elizabeth J.; Li, Yafang; Xie, Gang; Kosoy, Roman; Ransom, Michael; Sun, Ye; Bianchi, Ilaria; Schlicht, Erik M.; Lleo, Ana; Coltescu, Catalina; Bernuzzi, Francesca; Podda, Mauro; Lammert, Craig; Shigeta, Russell; Chan, Landon L.; Balschun, Tobias; Marconi, Maurizio; Cusi, Daniele; Heathcote, E. Jenny; Mason, Andrew L.; Myers, Robert P.; Milkiewicz, Piotr; Odin, Joseph A.; Luketic, Velimir A.; Bacon, Bruce R.; Bodenheimer, Henry C.; Liakina, Valentina; Vincent, Catherine; Levy, Cynthia; Franke, Andre; Gregersen, Peter K.; Bossa, Fabrizio; Eric Gershwin, M.; De Andrade, Mariza; Amos, Christopher I.; Lazaridis, Konstantinos N.; Seldin, Michael F.; Siminovitch, Katherine A.

In: Human Molecular Genetics, Vol. 21, No. 23, dds359, 01.12.2012, p. 5209-5221.

Research output: Contribution to journalArticle

Juran, BD, Hirschfield, GM, Invernizzi, P, Atkinson, EJ, Li, Y, Xie, G, Kosoy, R, Ransom, M, Sun, Y, Bianchi, I, Schlicht, EM, Lleo, A, Coltescu, C, Bernuzzi, F, Podda, M, Lammert, C, Shigeta, R, Chan, LL, Balschun, T, Marconi, M, Cusi, D, Heathcote, EJ, Mason, AL, Myers, RP, Milkiewicz, P, Odin, JA, Luketic, VA, Bacon, BR, Bodenheimer, HC, Liakina, V, Vincent, C, Levy, C, Franke, A, Gregersen, PK, Bossa, F, Eric Gershwin, M, De Andrade, M, Amos, CI, Lazaridis, KN, Seldin, MF & Siminovitch, KA 2012, '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', Human Molecular Genetics, vol. 21, no. 23, dds359, pp. 5209-5221. https://doi.org/10.1093/hmg/dds359
Juran, Brian D. ; Hirschfield, Gideon M. ; Invernizzi, Pietro ; Atkinson, Elizabeth J. ; Li, Yafang ; Xie, Gang ; Kosoy, Roman ; Ransom, Michael ; Sun, Ye ; Bianchi, Ilaria ; Schlicht, Erik M. ; Lleo, Ana ; Coltescu, Catalina ; Bernuzzi, Francesca ; Podda, Mauro ; Lammert, Craig ; Shigeta, Russell ; Chan, Landon L. ; Balschun, Tobias ; Marconi, Maurizio ; Cusi, Daniele ; Heathcote, E. Jenny ; Mason, Andrew L. ; Myers, Robert P. ; Milkiewicz, Piotr ; Odin, Joseph A. ; Luketic, Velimir A. ; Bacon, Bruce R. ; Bodenheimer, Henry C. ; Liakina, Valentina ; Vincent, Catherine ; Levy, Cynthia ; Franke, Andre ; Gregersen, Peter K. ; Bossa, Fabrizio ; Eric Gershwin, M. ; De Andrade, Mariza ; Amos, Christopher I. ; Lazaridis, Konstantinos N. ; Seldin, Michael F. ; Siminovitch, Katherine A. / 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. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 23. pp. 5209-5221.
@article{d4fcce66b4164bfcb81419c5a78ddbf9,
title = "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",
abstract = "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.",
author = "Juran, {Brian D.} and Hirschfield, {Gideon M.} and Pietro Invernizzi and Atkinson, {Elizabeth J.} and Yafang Li and Gang Xie and Roman Kosoy and Michael Ransom and Ye Sun and Ilaria Bianchi and Schlicht, {Erik M.} and Ana Lleo and Catalina Coltescu and Francesca Bernuzzi and Mauro Podda and Craig Lammert and Russell Shigeta and Chan, {Landon L.} and Tobias Balschun and Maurizio Marconi and Daniele Cusi and Heathcote, {E. Jenny} and Mason, {Andrew L.} and Myers, {Robert P.} and Piotr Milkiewicz and Odin, {Joseph A.} and Luketic, {Velimir A.} and Bacon, {Bruce R.} and Bodenheimer, {Henry C.} and Valentina Liakina and Catherine Vincent and Cynthia Levy and Andre Franke and Gregersen, {Peter K.} and Fabrizio Bossa and {Eric Gershwin}, M. and {De Andrade}, Mariza and Amos, {Christopher I.} and Lazaridis, {Konstantinos N.} and Seldin, {Michael F.} and Siminovitch, {Katherine A.}",
year = "2012",
month = "12",
day = "1",
doi = "10.1093/hmg/dds359",
language = "English",
volume = "21",
pages = "5209--5221",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "23",

}

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 - 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 - Eric Gershwin, M.

AU - De Andrade, 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.

UR - http://www.scopus.com/inward/record.url?scp=84869060864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84869060864&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds359

DO - 10.1093/hmg/dds359

M3 - Article

C2 - 22936693

AN - SCOPUS:84869060864

VL - 21

SP - 5209

EP - 5221

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 23

M1 - dds359

ER -