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PMID: 26394269 Published · epublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Nature communications ·Vol. 6 ·2015-09-22 ·Pages 8019

Cordell HJ, Han Y, Mells GF, Li Y, Hirschfield GM, Greene CS, Xie G, Juran BD, Zhu D, Qian DC, Floyd JA, Morley KI, Prati D, Lleo A, Cusi D, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Gershwin ME, Anderson CA, Lazaridis KN, Invernizzi P, Seldin MF, Sandford RN, Amos CI, Siminovitch KA

Abstract

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

MeSH Terms
Genome-Wide Association Study Humans Liver Cirrhosis, Biliary/genetics
Authors & Affiliations
26 authors, click to expand affiliations / ORCID
Cordell Heather J
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
Han Younghun
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
Mells George F
Academic Department of Medical Genetics, Cambridge University, Cambridge CB2 0QQ, UK.
Li Yafang
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
Hirschfield Gideon M
Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham B15 2TT, UK.
Greene Casey S
Department of Genetics, Institute for Quantitative Biomedical Sciences, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
Xie Gang
Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario M5G 1X5, Canada.
Juran Brian D
Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
Zhu Dakai
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
Qian David C
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
Floyd James A B
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. | William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.
Morley Katherine I
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. | Institute of Psychiatry, Psychology &Neuroscience, Kings College London, London SE5 8AF, UK.
Prati Daniele
Department of Transfusion Medicine and Hematology, Ospedale Alessandro Manzoni, Lecco 23900, Italy.
Lleo Ana
Center for Autoimmune Liver Diseases, IRCCS Instituto Clinico Humanitas, 20089 Rozzano, Italy.
Cusi Daniele
Università degli Studi di Milano, Milan 20129, Italy. | Istituto di Tecnologie Biomediche Consiglio Nazionale delle Ricerche, Via Fratelli Cervi, 93, 20090 Segrate, Milan, Italy.
Canadian-US PBC Consortium
Italian PBC Genetics Study Group
UK-PBC Consortium
Gershwin M Eric
University of California - Davis, Davis, California 95616, USA.
Anderson Carl A
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
Lazaridis Konstantinos N
Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
Invernizzi Pietro
Center for Autoimmune Liver Diseases, IRCCS Instituto Clinico Humanitas, 20089 Rozzano, Italy. | University of California - Davis, Davis, California 95616, USA.
Seldin Michael F
University of California - Davis, Davis, California 95616, USA.
Sandford Richard N
Academic Department of Medical Genetics, Cambridge University, Cambridge CB2 0QQ, UK.
Amos Christopher I
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
Siminovitch Katherine A
Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario M5G 1X5, Canada. | Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1X5. | Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 1X5. | Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1X5.
Investigators
438 investigators, click to expand
Schlicht Erik M
Lammert Craig
Atkinson Elizabeth J
Chan Landon L
de Andrade Mariza
Balschun Tobias
Mason Andrew L
Myers Robert P
Zhang Jinyi
Milkiewicz Piotr
Qu Jia
Odin Joseph A
Luketic Velimir A
Bacon Bruce R
Bodenheimer Henry C
Liakina Valentina
Vincent Catherine
Levy Cynthia
Gregersen Peter K
Almasio Piero L
Alvaro Domenico
Andreone Pietro
Andriulli Angelo
Barlassina Cristina
Battezzati Pier Maria
Benedetti Antonio
Bernuzzi Francesca
Bianchi Ilaria
Bragazzi Maria Consiglia
Brunetto Maurizia
Bruno Savino
Casella Giovanni
Coco Barbara
Colli Agostino
Colombo Massimo
Colombo Silvia
Cursaro Carmela
Crocè Lory Saveria
Crosignani Andrea
Donato Maria Francesca
Elia Gianfranco
Fabris Luca
Ferrari Carlo
Floreani Annarosa
Foglieni Barbara
Fontana Rosanna
Galli Andrea
Lazzari Roberta
Macaluso Fabio
Malinverno Federica
Marra Fabio
Marzioni Marco
Mattalia Alberto
Montanari Renzo
Morini Lorenzo
Morisco Filomena
Hani S Mousa
Muratori Luigi
Muratori Paolo
Niro Grazia A
Palmieri Vincenzo O
Picciotto Antonio
Podda Mauro
Portincasa Piero
Ronca Vincenzo
Rosina Floriano
Rossi Sonia
Sogno Ilaria
Spinzi Giancarlo
Spreafico Marta
Strazzabosco Mario
Tarallo Sonia
Tarocchi Mirko
Tiribelli Claudio
Toniutto Pierluigi
Vinci Maria
Zuin Massimo
Ch'ng Chin Lye
Rahman Mesbah
Yapp Tom
Sturgess Richard
Healey Christopher
Czajkowski Marek
Gunasekera Anton
Gyawali Pranab
Premchand Purushothaman
Kapur Kapil
Marley Richard
Foster Graham
Watson Alan
Dias Aruna
Subhani Javaid
Harvey Rory
McCorry Roger
Ramanaden David
Gasem Jaber
Evans Richard
Mathialahan Thiriloganathan
Shorrock Christopher
Lipscomb George
Southern Paul
Tibble Jeremy
Gorard David
Palegwala Altaf
Jones Susan
Carbone Marco
Dawwas Mohamed
Alexander Graeme
Dolwani Sunil
Prince Martin
Foxton Matthew
Elphick David
Mitchison Harriet
Gooding Ian
Karmo Mazn
Saksena Sushma
Mendall Mike
Patel Minesh
Ede Roland
Austin Andrew
Sayer Joanna
Hankey Lorraine
Hovell Christopher
Fisher Neil
Carter Martyn
Koss Konrad
Piotrowicz Andrzej
Grimley Charles
Neal David
Lim Guan
Levi Sass
Ala Aftab
Broad Andrea
Saeed Athar
Wood Gordon
Brown Jonathan
Wilkinson Mark
Gordon Harriet
Ramage John
Ridpath Jo
Ngatchu Theodore
Grover Bob
Shaukat Syed
Shidrawi Ray
Abouda George
Ali Faiz
Rees Ian
Salam Imroz
Narain Mark
Brown Ashley
Taylor-Robinson Simon
Williams Simon
Grellier Leonie
Banim Paul
Das Debashis
Chilton Andrew
Heneghan Michael
Curtis Howard
Gess Markus
Drake Ian
Aldersley Mark
Davies Mervyn
Jones Rebecca
McNair Alastair
Srirajaskanthan Raj
Pitcher Maxton
Sen Sambit
Bird George
Barnardo Adrian
Kitchen Paul
Yoong Kevin
Chirag Oza
Sivaramakrishnan Nurani
MacFaul George
Jones David
Shah Amir
Evans Chris
Saha Subrata
Pollock Katharine
Bramley Peter
Mukhopadhya Ashis
Fraser Andrew
Mills Peter
Shallcross Christopher
Campbell Stewart
Bathgate Andrew
Shepherd Alan
Dillon John
Rushbrook Simon
Przemioslo Robert
Macdonald Christopher
Metcalf Jane
Shmueli Udi
Davis Andrew
Naqvi Asifabbas
Lee Tom
Ryder Stephen D
Collier Jane
Klass Howard
Ninkovic Mary
Cramp Matthew
Sharer Nicholas
Aspinall Richard
Goggin Patrick
Ghosh Deb
Douds Andrew
Hoeroldt Barbara
Booth Jonathan
Williams Earl
Hussaini Hyder
Stableforth William
Ayres Reuben
Thorburn Douglas
Marshall Eileen
Burroughs Andrew
Mann Steven
Lombard Martin
Richardson Paul
Patanwala Imran
Maltby Julia
Brookes Matthew
Mathew Ray
Vyas Samir
Singhal Saket
Gleeson Dermot
Misra Sharat
Butterworth Jeff
George Keith
Harding Tim
Douglass Andrew
Panter Simon
Shearman Jeremy
Bray Gary
Butcher Graham
Forton Daniel
Mclindon John
Cowan Matthew
Whatley Gregory
Mandal Aditya
Gupta Hemant
Sanghi Pradeep
Jain Sanjiv
Pereira Steve
Prasad Geeta
Watts Gill
Wright Mark
Neuberger James
Gordon Fiona
Unitt Esther
Grant Allister
Delahooke Toby
Higham Andrew
Brind Alison
Cox Mark
Ramakrishnan Subramaniam
King Alistair
Collins Carole
Whalley Simon
Li Andy
Fraser Jocelyn
Bell Andrew
Wong Voi Shim
Singhal Amit
Gee Ian
Ang Yeng
Ransford Rupert
Gotto James
Millson Charles
Bowles Jane
Thomas Caradog
Harrison Melanie
Galaska Roman
Kendall Jennie
Whiteman Jessica
Lawlor Caroline
Gray Catherine
Elliott Keith
Mulvaney-Jones Caroline
Hobson Lucie
Van Duyvenvoorde Greta
Loftus Alison
Seward Katie
Penn Ruth
Maiden Jane
Damant Rose
Hails Janeane
Cloudsdale Rebecca
Silvestre Valeria
Glenn Sue
Dungca Eleanor
Wheatley Natalie
Doyle Helen
Kent Melanie
Hamilton Caroline
Braim Delyth
Wooldridge Helen
Abrahams Rachel
Paton Alison
Lancaster Nicola
Gibbins Andrew
Hogben Karen
Desousa Phillipa
Muscariu Florin
Musselwhite Janine
McKay Alexandra
Tan LaiTing
Foale Carole
Brighton Jacqueline
Flahive Kerry
Nambela Estelle
Townshend Paula
Ford Chris
Holder Sophie
Palmer Caroline
Featherstone James
Nasseri Mariam
Sadeghian Joy
Williams Bronwen
Thomas Carol
Rolls Sally-Ann
Hynes Abigail
Duggan Claire
Jones Sarah
Crossey Mary
Stansfield Glynis
MacNicol Carolyn
Wilkins Joy
Wilhelmsen Elva
Raymode Parizade
Lee Hye-Jeong
Durant Emma
Bishop Rebecca
Ncube Noma
Tripoli Sherill
Casey Rebecca
Cowley Caroline
Miller Richard
Houghton Kathryn
Ducker Samantha
Wright Fiona
Bird Bridget
Baxter Gwen
Keggans Janie
Hughes Maggie
Grieve Emma
Young Karin
Williams D
Ocker Kate
Hines Frances
Martin Kirsty
Innes Caron
Valliani Talal
Fairlamb Helen
Thornthwaite Sarah
Eastick Anne
Tanqueray Elizabeth
Morrison Jennifer
Holbrook Becky
Browning Julie
Walker Kirsten
Congreave Susan
Verheyden Juliette
Slininger Susan
Stafford Lizzie
O'Donnell Denise
Ainsworth Mark
Lord Susan
Kent Linda
March Linda
Dickson Christine
Simpson Diane
Longhurst Beverley
Hayes Maria
Shpuza Ervin
White Nikki
Besley Sarah
Pearson Sallyanne
Wright Alice
Jones Linda
Gunter Emma
Dewhurst Hannah
Fouracres Anna
Farrington Liz
Graves Lyn
Marriott Suzie
Leoni Marina
Tyrer David
Martin Kate
Dali-Kemmery Lola
Lambourne Victoria
Green Marie
Sirdefield Dawn
Amor Kelly
Colley Julie
Shinder Bal
Jones Jayne
Mills Marisa
Carnahan Mandy
Taylor Natalie
Boulton Kerenza
Tregonning Julie
Brown Carly
Clifford Gayle
Archer Emily
Hamilton Maria
Curtis Janette
Shewan Tracey
Walsh Sue
Warner Karen
Netherton Kimberley
Mupudzi Mcdonald
Gunson Bridget
Gitahi Jane
Gocher Denise
Batham Sally
Pateman Hilary
Desmennu Senayon
Conder Jill
Clement Darren
Gallagher Susan
Orpe Jacky
Chan PuiChing
Currie Lynn
O'Donohoe Lynn
Oblak Metod
Morgan Lisa
Quinn Marie
Amey Isobel
Baird Yolanda
Cotterill Donna
Cumlat Lourdes
Winter Louise
Greer Sandra
Spurdle Katie
Allison Joanna
Dyer Simon
Sweeting Helen
Kordula Jean
References (31)
31 references, click to expand
  1. Genomic control for association studies.
    Biometrics. 1999 Dec;55(4):997-1004 PMID: 11315092
  2. Principal components analysis corrects for stratification in genome-wide association studies.
    Nat Genet. 2006 Aug;38(8):904-9 PMID: 16862161
  3. A new multipoint method for genome-wide association studies by imputation of genotypes.
    Nat Genet. 2007 Jul;39(7):906-13 PMID: 17572673
  4. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  5. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.
    N Engl J Med. 2009 Jun 11;360(24):2544-55 PMID: 19458352
  6. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.
    Nat Protoc. 2009;4(7):1073-81 PMID: 19561590
  7. ProbABEL package for genome-wide association analysis of imputed data.
    BMC Bioinformatics. 2010;11:134 PMID: 20233392
  8. A method and server for predicting damaging missense mutations.
    Nat Methods. 2010 Apr;7(4):248-9 PMID: 20354512
  9. Meta-analysis and imputation refines the association of 15q25 with smoking quantity.
    Nat Genet. 2010 May;42(5):436-40 PMID: 20418889
  10. i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study.
    Nucleic Acids Res. 2010 Jul;38(Web Server issue):W90-5 PMID: 20435672
  11. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis.
    Nat Genet. 2010 Aug;42(8):655-7 PMID: 20639879
  12. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis.
    Nat Genet. 2010 Aug;42(8):658-60 PMID: 20639880
  13. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies.
    Bioinformatics. 2010 Oct 1;26(19):2474-6 PMID: 20702402
  14. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes.
    Genet Epidemiol. 2010 Dec;34(8):816-34 PMID: 21058334
  15. GCTA: a tool for genome-wide complex trait analysis.
    Am J Hum Genet. 2011 Jan 7;88(1):76-82 PMID: 21167468
  16. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.
    Nat Genet. 2011 Apr;43(4):329-32 PMID: 21399635
  17. seeQTL: a searchable database for human eQTLs.
    Bioinformatics. 2012 Feb 1;28(3):451-2 PMID: 22171328
  18. A linear complexity phasing method for thousands of genomes.
    Nat Methods. 2012 Feb;9(2):179-81 PMID: 22138821
  19. The accessible chromatin landscape of the human genome.
    Nature. 2012 Sep 6;489(7414):75-82 PMID: 22955617
  20. Systematic localization of common disease-associated variation in regulatory DNA.
    Science. 2012 Sep 7;337(6099):1190-5 PMID: 22955828
  21. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.
    Nat Genet. 2012 Oct;44(10):1137-41 PMID: 22961000
  22. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.
    Am J Hum Genet. 2012 Oct 5;91(4):721-8 PMID: 23000144
  23. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.
    J Hepatol. 2012 Nov;57(5):1044-51 PMID: 22796894
  24. 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.
    Hum Mol Genet. 2012 Dec 1;21(23):5209-21 PMID: 22936693
  25. Integrative annotation of chromatin elements from ENCODE data.
    Nucleic Acids Res. 2013 Jan;41(2):827-41 PMID: 23221638
  26. The immunobiology and pathophysiology of primary biliary cirrhosis.
    Annu Rev Pathol. 2013 Jan 24;8:303-30 PMID: 23347352
  27. Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.
    Nat Genet. 2013 Jul;45(7):822-4 PMID: 23708191
  28. Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements.
    Am J Hum Genet. 2013 Nov 7;93(5):876-90 PMID: 24183450
  29. DGIdb: mining the druggable genome.
    Nat Methods. 2013 Dec;10(12):1209-10 PMID: 24122041
  30. Joint analysis of functional genomic data and genome-wide association studies of 18 human traits.
    Am J Hum Genet. 2014 Apr 3;94(4):559-73 PMID: 24702953
  31. Genetic and epigenetic fine mapping of causal autoimmune disease variants.
    Nature. 2015 Feb 19;518(7539):337-43 PMID: 25363779
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms9019
Published
2015-09-22
Epub
2015-00-22
Pages
8019
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4580981
Subset
IM
Grants
NIGMS NIH HHS · P20 GM103534 · United States
Wellcome Trust · 102858/Z/13/Z · United Kingdom
NIDDK NIH HHS · R01 DK080670 · United States
NIDDK NIH HHS · R01DK80670 · United States
Medical Research Council · MR/L001489/1 · United Kingdom
NCATS NIH HHS · UL1 TR001108 · United States
NCI NIH HHS · P30 CA023108 · United States
NIDDK NIH HHS · R01DK091823 · United States
NIDDK NIH HHS · R01 DK091823 · United States
Wellcome Trust · 085925 · United Kingdom
Wellcome Trust · 085475 · United Kingdom
Wellcome Trust · United Kingdom
NIGMS NIH HHS · GM103534 · United States
Wellcome Trust · 090355 · United Kingdom
CIHR · MOP74621 · Canada
Medical Research Council · G0800460 · United Kingdom
Wellcome Trust · 087436 · United Kingdom
External Links
PubMed source DOI: 10.1038/ncomms9019 PMC Full Text View journal details
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