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

Cordell, Heather J.; Han, Younghun; Mells, George F.; Yafang, Li; Hirschfield, Gideon M.; Greene, Casey S.; Xie, Gang; Juran 7, Brian D.; Dakai Zhu, 2; Qian 2, David C.; Floyd, James A. B.; Morley, Katherine I.; Daniele Prati 11,; Ana Lleo 12,; Cusi, Daniele; Eric Gershwin 15, M.; Anderson 8, Carl A.; Lazaridis 7, Konstantinos N.; Invernizzi, Pietro; Seldin 15, Michael F.; Sandford, Richard N.; Amos 2, Christopher I.; Siminovitch, Katherine A.; Schlicht 7, Erik M.; Craig Lammert, 7; Atkinson 19, Elizabeth J.; Chan 19, Landon L.; Mariza De Andrade 19,; Tobias Balschun 20,; Mason 21, Andrew L.; Myers 22, Robert P.; Jinyi Zhang 23,; Piotr Milkiewicz 24,; Jia Qu 25,; Odin 26, Joseph A.; Luketic 27, Velimir A.; Bacon 28, Bruce R.; Bodenheimer Jr 29, Henry C.; Valentina Liakina 30,; Catherine Vincent 31,; Cynthia Levy 32,; Gregersen, Peter K.; Almasio, 33 Piero L.; Domenico Alvaro 35,; Pietro Andreone 36,; Angelo Andriulli 37,; Cristina Barlassina 38,; Pier Maria Battezzati 39,; Antonio Benedetti 40,; Francesca Bernuzzi 41,; Ilaria Bianchi 41,; Maria Consiglia Bragazzi 42,; Maurizia Brunetto 43,; Savino Bruno 41,; Giovanni Casella 44,; Barbara Coco 43,; Agostino Colli 45,; Massimo Colombo 46,; Silvia Colombo 47,; Carmela Cursaro 36,; Lory Saveria Croce, ` 48; Andrea Crosignani 39,; Maria Francesca Donato 46,; Gianfranco Elia 49,; Luca Fabris 50,; Carlo Ferrari 49,; Annarosa Floreani 51,; Barbara Foglieni 11,; Rosanna Fontana 37,; Galli, Andrea; Roberta Lazzari 51,; Fabio Macaluso 34,; Federica Malinverno 46,; Marra, Fabio; Marco Marzioni 40,; Alberto Mattalia 54,; Renzo Montanari 55,; Lorenzo Morini 56,; Filomena Morisco 57,; Mousa Hani S., 41; Luigi Muratori 36,; Paolo Muratori 36,; Niro 37, Grazia A.; Palmieri 58, Vincenzo O.; Antonio Picciotto 59,; Mauro Podda 41,; Piero Portincasa 58,; Vincenzo Ronca 41,; Floriano Rosina 60,; Sonia Rossi 41,; Ilaria Sogno 41,; Giancarlo Spinzi 61,; Marta Spreafico 11,; Strazzabosco, Mario; Sonia Tarallo 60,; Tarocchi, Mirko; Claudio Tiribelli 48,; Pierluigi Toniutto 64,; Maria Vinci 65,; Zuin, Massimo; Chin Lye Ch’Ng,; Mesbah Rahman 68,; Tom Yapp 69,; Richard Sturgess 70,; Christopher Healey 71,; Czajkowski, Marek; Gunasekera, Anton; Pranab Gyawali 77,; Purushothaman Premchand 78,; Kapil Kapur 79,; Richard Marley 80,; Graham Foster 80,; Alan Watson 81,; Aruna Dias 82,; Javaid Subhani 83,; Rory Harvey 84,; Roger Mccorry 85,; David Ramanaden 86,; Jaber Gasem 87,; Richard Evans 88,; Thiriloganathan Mathialahan 89,; Christopher Shorrock 90,; George Lipscomb 91,; Paul Southern 92,; Jeremy Tibble 93,; 94,; Gorard, David; Altaf Palegwala 98,; Jones, Susan; Marco Carbone 101,; Mohamed Dawwas 101,; Graeme Alexander 101,; Dolwani, Sunil; Martin Prince 104,; Matthew Foxton 105,; David Elphick 106,; Harriet Mitchison 107,; Ian Gooding 108,; Mazn Karmo 109,; Saksena, Sushma; Mendall, Mike; Patel, Minesh; Ede, Roland; Andrew Austin 119,; Sayer, Joanna; Lorraine Hankey 122,; Christopher Hovell 122,; Neil Fisher 123,; Carter, Martyn; Konrad Koss 126,; Piotrowicz, Andrzej; Grimley, Charles; Neal, David; Guan Lim 135,; Levi, Sass; Aftab Ala 138,; Andrea Broad 139,; Athar Saeed 139,; Gordon Wood 140,; Brown, Jonathan; Wilkinson, Mark; Harriet Gordon 145,; John Ramage 146,; Jo Ridpath 147,; Ngatchu, Theodore; Bob Grover 151,; Syed Shaukat 152,; Ray Shidrawi 153,; Abouda, George; Faiz Ali 156,; Ian Rees 157,; Imroz Salam 158,; Mark Narain 159,; Brown, Ashley; Simon Taylor Robinson 162,; Simon Williams 163,; Leonie Grellier 164,; Paul Banim 165,; Debasish Das 166,; Andrew Chilton 166,; Michael Heneghan 167,; Curtis, Howard; Markus Gess 170,; Drake, Ian; Aldersley, Mark; Davies, Mervyn; Jones, Rebecca; Alastair Mcnair 175,; Raj Srirajaskanthan 176,; Pitcher, Maxton; Sambit Sen 179,; Bird, George; Adrian Barnardo 182,; Paul Kitchen 182,; Kevin Yoong 183,; Chirag, Oza; Nurani Sivaramakrishnan 186,; George Macfaul 187,; David Jones 188,; Amir Shah 189,; Chris Evans 190,; Subrata Saha 191,; Pollock, Katharine; Bramley, Peter; Mukhopadhya, Ashis; Fraser, Andrew; Mills, Peter; Shallcross, Christopher; Campbell, Stewart; Bathgate, Andrew; Alan Shepherd 213,; John Dillon 214,; Simon Rushbrook 215,; Robert Przemioslo 216 Christopher Macdonald,; Metcalf, Jane; Udi Shmueli 221,; Davis, Andrew; Naqvi, Asifabbas; Lee, Tom; Ryder, Stephen D.; Jane Collier 231,; Klass, Howard; Ninkovic, Mary; Matthew Cramp 238,; Nicholas Sharer 239,; Richard Aspinall 240,; Patrick Goggin 240,; Ghosh, Deb; Andrew Douds 243,; Barbara Hoeroldt 244,; Jonathan Booth 245,; Earl Williams 246,; Hyder Hussaini 247,; William Stableforth 247,; Reuben Ayres 248,; Douglas Thorburn 249,; Eileen Marshall 249,; Andrew Burroughs 249,; Mann, Steven; Martin Lombard 252,; Paul Richardson 252,; Imran Patanwala 252,; Julia Maltby 253,; Matthew Brookes 254,; Mathew, Ray; Samir Vyas 257,; Saket Singhal 258,; Gleeson, Dermot; Misra, Sharat; Butterworth, Jeff; Keith George 265,; Harding, Tim; Douglass, Andrew; Simon Panter 270,; Jeremy Shearman 271,; Gary Bray 272,; Butcher, Graham; Daniel Forton 275,; Mclindon, John; Matthew Cowan 279,; Gregory Whatley 280,; Mandal, Aditya; Gupta, Hemant; Sanghi, Pradeep; Sanjiv Jain 283,; Steve Pereira 284,; Geeta Prasad 285,; Gill Watts 285,; Mark Wright 286,; James Neuberger 287,; Fiona Gordon 288,; Esther Unitt 289,; Grant, Allister; Delahooke, Toby; Andrew Higham 293,; Alison Brind 294,; Mark Cox 295,; Subramaniam Ramakrishnan 296,; King, Alistair; Carole Collins 300,; Whalley, Simon; Andy Li 303,; Jocelyn Fraser 304,; Andrew Bell 305,; Voi Shim Wong 306,; Singhal, Amit; Gee, Ian; Yeng Ang 312,; Rupert Ransford 313,; James Gotto 314,; Millson, Charles; Jane Bowles 318,; Thomas, Caradog; Melanie Harrison 70,; Roman Galaska 71,; Kendall, Jennie; Whiteman, Jessica; Lawlor, Caroline; Gray, Catherine; Keith Elliott 79,; Caroline Mulvaney Jones,; Hobson, Lucie; Greta Van Duyvenvoorde 90,; Alison Loftus 91,; Katie Seward 92,; Penn, Ruth; Jane Maiden 98,; Rose Damant 98,; Janeane Hails 101,; Cloudsdale, Rebecca; Valeria Silvestre 105,; Sue Glenn 106,; Eleanor Dungca 107,; Natalie Wheatley 108,; Helen Doyle 109,; Kent, Melanie; Hamilton, Caroline; Braim, Delyth; Helen Wooldridge 117,; Rachel Abrahams 117,; Alison Paton 119,; Lancaster, Nicola; Andrew Gibbins 122,; Karen Hogben 122,; Desousa, Phillipa; Muscariu, Florin; Musselwhite, Janine; Alexandra Mckay 132,; Laiting Tan 135,; Carole Foale 138,; Jacqueline Brighton 138,; Kerry Flahive 140,; Nambela, Estelle; Townshend, Paula; Ford, Chris; Holder, Sophie; Palmer, Caroline; James Featherstone 147,; Mariam Nasseri 151,; Joy Sadeghian 153,; Williams, Bronwen; Carol Thomas 156,; Sally Ann Rolls 156,; Abigail Hynes 159,; Claire Duggan 159,; Sarah Jones 159,; Crossey, Mary; Glynis Stansfield 163,; Carolyn Macnicol 163,; Joy Wilkins 164,; Elva Wilhelmsen 165,; Parizade Raymode 166,; Hye Jeong Lee 167,; Durant, Emma; Bishop, Rebecca; Ncube, Noma; Tripoli, Sherill; Casey, Rebecca; Caroline Cowley 182,; Richard Miller 183,; Kathryn Houghton 188,; Samantha Ducker 188,; Fiona Wright 189,; Bridget Bird 191,; Gwen Baxter 191,; Janie Keggans 191,; Hughes, Maggie; Emma Grieve 196,; Karin Young 196,; Williams 197, D.; Kate Ocker 199,; Hines, Frances; Martin, Kirsty; Innes, Caron; Talal Valliani 216,; Fairlamb, Helen; Thornthwaite, Sarah; Eastick, Anne; Elizabeth Tanqueray 221,; Jennifer Morrison 222,; Becky Holbrook 222,; Browning, Julie; Walker, Kirsten; Congreave, Susan; Verheyden, Juliette; Slininger, Susan; Lizzie Stafford 231,; Denise O’Donnell 231,; Mark Ainsworth 231,; Susan Lord 118,; Kent, Linda; Linda March 238,; Christine Dickson 239,; Diane Simpson 239,; Beverley Longhurst 240,; Maria Hayes 240,; Shpuza, Ervin; White, Nikki; Besley, Sarah; Sallyanne Pearson 244,; Alice Wright 245,; Linda Jones 245,; Emma Gunter 246,; Hannah Dewhurst 246,; Anna Fouracres 247,; Liz Farrington 247,; Lyn Graves 247,; Suzie Marriott 248,; Marina Leoni 249,; David Tyrer 252,; Kate Martin 252,; Lola Dali Kemmery 253,; Victoria Lambourne 253,; Marie Green 254,; Sirdefield, Dawn; Kelly Amor 255,; Julie Colley 258,; Bal Shinder 258,; Jayne Jones 260,; Marisa Mills 260,; Carnahan, Mandy; Natalie Taylor 265,; Kerenza Boulton 265,; Tregonning, Julie; Carly Brown 270,; Gayle Clifford 270,; Emily Archer 271,; Hamilton, Maria; Janette Curtis 278,; Tracey Shewan 279,; Sue Walsh 280,; Warner, Karen; Kimberley Netherton 283,; Mcdonald Mupudzi 286,; Bridget Gunson 287,; Jane Gitahi 288,; Denise Gocher 289,; Batham, Sally; Pateman, Hilary; Desmennu, Senayon; Jill Conder 293,; Darren Clement 294,; Susan Gallagher 294,; Jacky Orpe 256,; Puiching Chan 296,; Currie, Lynn; O’Donohoe, Lynn; Metod Oblak 300,; Lisa Morgan 302,; Marie Quinn 303,; Isobel Amey 304,; Yolanda Baird 304,; Donna Cotterill 305,; Lourdes Cumlat 306,; Louise Winter 312,; Sandra Greer 312,; Spurdle, Katie; Allison, Joanna; Dyer, Simon; Sweeting, Helen; Kordula, Jean

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.

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways / Heather J. Cordell, Younghun Han, George F. Mells, Yafang Li, Gideon M. Hirschfield, Casey S. Greene, Gang Xie, Brian D. Juran 7 , Dakai Zhu 2 , David C. Qian 2 , James A.B. Floyd , Katherine I. Morley , Daniele Prati 11 , Ana Lleo 12 , Daniele Cusi , M. Eric Gershwin 15 , Carl A. Anderson 8 , Konstantinos N. Lazaridis 7 , Pietro Invernizzi , Michael F. Seldin 15 , et al.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - ELETTRONICO. - (2015), pp. 1-11.