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Nat Commun. 2015 Sep 22;6:8019. doi: 10.1038/ncomms9019.

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

Collaborators (438)

Schlicht EM, Lammert C, Atkinson EJ, Chan LL, de Andrade M, Balschun T, Mason AL, Myers RP, Zhang J, Milkiewicz P, Qu J, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC Jr, Liakina V, Vincent C, Levy C, Gregersen PK, Almasio PL, Alvaro D, Andreone P, Andriulli A, Barlassina C, Battezzati PM, Benedetti A, Bernuzzi F, Bianchi I, Bragazzi MC, Brunetto M, Bruno S, Casella G, Coco B, Colli A, Colombo M, Colombo S, Cursaro C, Crocè LS, Crosignani A, Donato MF, Elia G, Fabris L, Ferrari C, Floreani A, Foglieni B, Fontana R, Galli A, Lazzari R, Macaluso F, Malinverno F, Marra F, Marzioni M, Mattalia A, Montanari R, Morini L, Morisco F, Hani S M, Muratori L, Muratori P, Niro GA, Palmieri VO, Picciotto A, Podda M, Portincasa P, Ronca V, Rosina F, Rossi S, Sogno I, Spinzi G, Spreafico M, Strazzabosco M, Tarallo S, Tarocchi M, Tiribelli C, Toniutto P, Vinci M, Zuin M, Ch'ng CL, Rahman M, Yapp T, Sturgess R, Healey C, Czajkowski M, Gunasekera A, Gyawali P, Premchand P, Kapur K, Marley R, Foster G, Watson A, Dias A, Subhani J, Harvey R, McCorry R, Ramanaden D, Gasem J, Evans R, Mathialahan T, Shorrock C, Lipscomb G, Southern P, Tibble J, Gorard D, Palegwala A, Jones S, Carbone M, Dawwas M, Alexander G, Dolwani S, Prince M, Foxton M, Elphick D, Mitchison H, Gooding I, Karmo M, Saksena S, Mendall M, Patel M, Ede R, Austin A, Sayer J, Hankey L, Hovell C, Fisher N, Carter M, Koss K, Piotrowicz A, Grimley C, Neal D, Lim G, Levi S, Ala A, Broad A, Saeed A, Wood G, Brown J, Wilkinson M, Gordon H, Ramage J, Ridpath J, Ngatchu T, Grover B, Shaukat S, Shidrawi R, Abouda G, Ali F, Rees I, Salam I, Narain M, Brown A, Taylor-Robinson S, Williams S, Grellier L, Banim P, Das D, Chilton A, Heneghan M, Curtis H, Gess M, Drake I, Aldersley M, Davies M, Jones R, McNair A, Srirajaskanthan R, Pitcher M, Sen S, Bird G, Barnardo A, Kitchen P, Yoong K, Chirag O, Sivaramakrishnan N, MacFaul G, Jones D, Shah A, Evans C, Saha S, Pollock K, Bramley P, Mukhopadhya A, Fraser A, Mills P, Shallcross C, Campbell S, Bathgate A, Shepherd A, Dillon J, Rushbrook S, Przemioslo R, Macdonald C, Metcalf J, Shmueli U, Davis A, Naqvi A, Lee T, Ryder SD, Collier J, Klass H, Ninkovic M, Cramp M, Sharer N, Aspinall R, Goggin P, Ghosh D, Douds A, Hoeroldt B, Booth J, Williams E, Hussaini H, Stableforth W, Ayres R, Thorburn D, Marshall E, Burroughs A, Mann S, Lombard M, Richardson P, Patanwala I, Maltby J, Brookes M, Mathew R, Vyas S, Singhal S, Gleeson D, Misra S, Butterworth J, George K, Harding T, Douglass A, Panter S, Shearman J, Bray G, Butcher G, Forton D, Mclindon J, Cowan M, Whatley G, Mandal A, Gupta H, Sanghi P, Jain S, Pereira S, Prasad G, Watts G, Wright M, Neuberger J, Gordon F, Unitt E, Grant A, Delahooke T, Higham A, Brind A, Cox M, Ramakrishnan S, King A, Collins C, Whalley S, Li A, Fraser J, Bell A, Wong VS, Singhal A, Gee I, Ang Y, Ransford R, Gotto J, Millson C, Bowles J, Thomas C, Harrison M, Galaska R, Kendall J, Whiteman J, Lawlor C, Gray C, Elliott K, Mulvaney-Jones C, Hobson L, Van Duyvenvoorde G, Loftus A, Seward K, Penn R, Maiden J, Damant R, Hails J, Cloudsdale R, Silvestre V, Glenn S, Dungca E, Wheatley N, Doyle H, Kent M, Hamilton C, Braim D, Wooldridge H, Abrahams R, Paton A, Lancaster N, Gibbins A, Hogben K, Desousa P, Muscariu F, Musselwhite J, McKay A, Tan L, Foale C, Brighton J, Flahive K, Nambela E, Townshend P, Ford C, Holder S, Palmer C, Featherstone J, Nasseri M, Sadeghian J, Williams B, Thomas C, Rolls SA, Hynes A, Duggan C, Jones S, Crossey M, Stansfield G, MacNicol C, Wilkins J, Wilhelmsen E, Raymode P, Lee HJ, Durant E, Bishop R, Ncube N, Tripoli S, Casey R, Cowley C, Miller R, Houghton K, Ducker S, Wright F, Bird B, Baxter G, Keggans J, Hughes M, Grieve E, Young K, Williams D, Ocker K, Hines F, Martin K, Innes C, Valliani T, Fairlamb H, Thornthwaite S, Eastick A, Tanqueray E, Morrison J, Holbrook B, Browning J, Walker K, Congreave S, Verheyden J, Slininger S, Stafford L, O'Donnell D, Ainsworth M, Lord S, Kent L, March L, Dickson C, Simpson D, Longhurst B, Hayes M, Shpuza E, White N, Besley S, Pearson S, Wright A, Jones L, Gunter E, Dewhurst H, Fouracres A, Farrington L, Graves L, Marriott S, Leoni M, Tyrer D, Martin K, Dali-Kemmery L, Lambourne V, Green M, Sirdefield D, Amor K, Colley J, Shinder B, Jones J, Mills M, Carnahan M, Taylor N, Boulton K, Tregonning J, Brown C, Clifford G, Archer E, Hamilton M, Curtis J, Shewan T, Walsh S, Warner K, Netherton K, Mupudzi M, Gunson B, Gitahi J, Gocher D, Batham S, Pateman H, Desmennu S, Conder J, Clement D, Gallagher S, Orpe J, Chan P, Currie L, O'Donohoe L, Oblak M, Morgan L, Quinn M, Amey I, Baird Y, Cotterill D, Cumlat L, Winter L, Greer S, Spurdle K, Allison J, Dyer S, Sweeting H, Kordula J.

Author information

1
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
2
Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03755, USA.
3
Academic Department of Medical Genetics, Cambridge University, Cambridge CB2 0QQ, UK.
4
Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham B15 2TT, UK.
5
Department of Genetics, Institute for Quantitative Biomedical Sciences, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
6
Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario M5G 1X5, Canada.
7
Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
8
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
9
William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.
10
Institute of Psychiatry, Psychology &Neuroscience, Kings College London, London SE5 8AF, UK.
11
Department of Transfusion Medicine and Hematology, Ospedale Alessandro Manzoni, Lecco 23900, Italy.
12
Center for Autoimmune Liver Diseases, IRCCS Instituto Clinico Humanitas, 20089 Rozzano, Italy.
13
Università degli Studi di Milano, Milan 20129, Italy.
14
Istituto di Tecnologie Biomediche Consiglio Nazionale delle Ricerche, Via Fratelli Cervi, 93, 20090 Segrate, Milan, Italy.
15
University of California - Davis, Davis, California 95616, USA.
16
Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1X5.
17
Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 1X5.
18
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1X5.

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.

PMID:
26394269
PMCID:
PMC4580981
DOI:
10.1038/ncomms9019
[Indexed for MEDLINE]
Free PMC Article

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