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International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways
Heather J. Cordell, Younghun Han, George Mells, Yafang Li, Gideon M. Hirschfield, Casey S. Greene, Gang Xie, Brian D. Juran, Dakai Zhu, David C. Qian, James Floyd, Katherine I. Morley, Daniele Prati, Ana Lleò, Daniele Cusi, Erik M. Schlicht, Craig Lammert, Elizabeth J. Atkinson, Landon L. Chan, Mariza de Andrade, Tobias Balschun, Andrew L. Mason, Robert P. Myers, Jinyi Zhang, Piotr Milkiewicz, Jia Qu, Joseph A. Odin, Velimir A. Luketic, Bruce R. Bacon, Henry C. Bodenheimer, Valentina Liakina, Catherine Vincent, Cynthia Levy, Peter K. Gregersen, Piero Luigi Almasio, Domenico Alvaro, Pietro Andreoné, Angelo Andriulli, Cristina Barlassina, Pier Maria Battezzati, A. Benedetti, Francesca Bernuzzi, Ilaria Bianchi, Maria Consiglia Bragazzi, Maurizia Rossana Brunetto, Savino Bruno, Giovanni Casella, B. Coco, Agostino Colli, Massimo Colombo, Sílvia Colombo, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Maria Francesca Donato, G. Elia, Luca Fabris, Carlo Ferrari, Annarosa Floreani, Barbara Foglieni, Rosanna Fontana, Andrea Galli, Roberta Lazzari, Fabio Salvatore Macaluso, Federica Malinverno, Fabio Marra, Marco Marzioni, Alberto Mattalia, R. Montanari, Lorenzo Morini, Filomena Morisco, Hani S. Mousa, Luigi Muratori, Paolo Muratori, Grazia Anna Niro, Vincenzo Ostilio Palmieri, Mauro Podda, Piero Portincasa, Vincenzo Ronca, F. Rosina, Sonia Rossi, Ilaria Sogno, Giancarlo Spinzi, Marta Spreafico, Mario Strazzabosco, Sonia Tarallo, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Maria Cristina Vinci, Massimo Zuin, Chin Lye Ch’ng, Mesbah Rahman, Tom Yapp, Richard Sturgess, Christopher Healey, Marek Czajkowski, Anton Gunasekera, Pranab Gyawali, Purushothaman Premchand, Kapil Kapur, Richard Marley, Graham R. Foster, Alan Watson, Aruna Dias, Javaid Subhani, Rory Harvey, Roger McCorry, David Ramanaden, Jaber Gasem, Richard Evans, Thiriloganathan Mathialahan, C Shorrock, George Lipscomb, Paul Southern, Jeremy Tibble, Altaf Palegwala, Susan Jones, Marco Carbone, Mohamed Dawwas, Graeme Alexander, Sunil Dolwani, Martin Prince, Matthew Foxton, David Elphick, Harriet Mitchison, Ian Gooding, Mazn Karmo, Sushma Saksena, Mike Mendall, Minesh Patel, Roland Ede, Andrew Austin, Joanna Sayer, Lorraine Hankey, Christopher Hovell, Neil Fisher, Martyn Carter, Konrad Koss, Andrzej Piotrowicz, Charles Grimley, David E. Neal, Guan Lim, Sass Levi, Aftab Ala, Andrea Broad, Athar A. Saeed, Gordon Wood, Jonathan Brown, Mark Wilkinson, Harriet Gordon, John Ramage, Jo Ridpath, Theodore Ngatchu, Bob Grover, Syed Shahid Shaukat, Ray Shidrawi, George Abouda, Faiz Ali, Ian Rees, Imroz Salam, Mark Narain, Ashley Brown, Simon D. Taylor‐Robinson, Simon Williams, Leonie Grellier, Paul Banim, Andrew Chilton, Michael A. Heneghan, Howard J. Curtis, Markus Gess, Ian Drake, Mark Aldersley, Mervyn H. Davies, Rebecca Jones, Alastair McNair, Raj Srirajaskanthan, Maxton Pitcher, Sambit Sen, George Bird, Adrian Barnardo, Paul Kitchen, Kevin Yoong, Oza Chirag, Nurani Sivaramakrishnan, George MacFaul, David Jones, Amir Shah, Chris Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Andrew Fraser, Peter R. Mills, Christopher Shallcross, S. Campbell, Andrew Bathgate, Alan Shepherd, John Dillon, Simon Rushbrook, Robert Przemioslo, Christopher Macdonald, Jane Metcalf, Udi Shmueli, A. Davis, Asifabbas Naqvi, Tom Lee, Stephen Ryder, Jane Collier, Howard Klass, Mary Ninkovic, Matthew Cramp, Nicholas M. Sharer, Richard Aspinall, Patrick Goggin, Deb Ghosh, Andrew Douds, Barbara Hoeroldt, Jonathan Booth, Earl Williams, Hyder Hussaini, William Stableforth, Reuben Ayres, Douglas Thorburn, Eileen Marshall, Andrew K. Burroughs, Steven Mann, Martin Lombard, Paul Richardson, Imran Patanwala, Julia Maltby, Matthew Brookes, Ray Mathew, Samir Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, A. E. Douglass, Simon Panter, Jeremy Shearman, Gary Bray, Graham P. Butcher, Daniel Forton, John Mclindon, Matthew Cowan, Gregory Whatley, Aditya Mandal, Hemant Gupta, Pradeep Sanghi, Sanjiv Jain, Geeta Prasad, Gill Watts, Mark Wright, James Neuberger, F. Gordon, Esther Unitt, Allister Grant, Toby Delahooke, Andrew Higham, Alison Brind, Mark Cox, S. Ramakrishnan, Alistair King, C.D. Collins, Simon Whalley, Andrew A. Li, Jocelyn Fraser, A.J. Bell, Voi Shim Wong, Amit Singhal, Ian Gee, Yeng Ang, Rupert Ransford, James Gotto, Charles Millson, Jane Bowles, Caradog Thomas, Melanie Harrison, Roman Galaska, Jennie Kendall, Jessica Whiteman, Caroline Lawlor, Catherine Gray, Keith Elliott, Caroline Mulvaney-Jones, Lucie Hobson, Greta Van Duyvenvoorde, Alison Loftus, Katie Seward, Ruth Penn, Jane Maiden, Rose Damant, Janeane Hails, Rebecca Cloudsdale, Valéria Damasceno Silvestre, Sue Glenn, Eleanor Dungca, Natalie Wheatley, Helen Doyle, Melanie Kent, Caroline Hamilton, Delyth Braim, Helen Wooldridge, Rachel Abrahams, Alison Paton, Nicola Lancaster, Andrew Gibbins, Karen Hogben, Phillipa Desousa, Florin Muscariu, Janine Musselwhite, Alexandra McKay, LaiTing Tan, Carole Foale, Jacqueline Brighton, Kerry Flahive, Estelle Nambela, Paula Townshend, Christopher M. Ford, Sophie M. Holder, Caroline Palmer, James Featherstone, Mariam Nasseri, Joy Sadeghian, Bronwen Williams, Carol Thomas, Sally-Ann Rolls, Abigail Hynes, Claire Duggan, Sarah Jones, Mary M.E. Crossey, Glynis Stansfield, Carolyn MacNicol, Joy Wilkins, Elva Wilhelmsen, Parizade Raymode, Hye‐Jeong Lee, Emma Durant, Rebecca Bishop, Noma Ncube, Sherill Tripoli, Rebecca M. Casey, Caroline Cowley, Richard A. Miller, Kathryn Houghton, Samantha Ducker, Fiona Wright, Bridget Bird, Gwen Baxter, Janie Keggans, Maggie Hughes, Emma Grieve, Karin Young, Dewi Williams, Kate Ocker, Frances Hines, K. Martin, Caron Innes, Talal Valliani, Helen Fairlamb, Sarah Thornthwaite, Anne Eastick, Elizabeth Tanqueray, Jennifer Morrison, Becky Holbrook, Julie Browning, Kirsten Walker, Susan Congreave, Juliette Verheyden, Susan Slininger, Lizzie Stafford, Denise O’Donnell, Mark Ainsworth, Susan Lord, Linda March, Christine Dickson, Diane M. Simpson, Beverley Longhurst, Maria Hayes, Ervin Shpuza, Nikki White, Sarah Besley, Sallyanne Pearson, Alice Wright, Linda Jones, Emma Gunter, Hannah F. Dewhurst, Anna Fouracres, Liz Farrington, Lyn Graves, Suzie Marriott, Marina Leoni, David Tyrer, Kate Martin, Lola Dali-Kemmery, Victoria Lambourne, Marie Green, Dawn Sirdefield, Kelly Amor, Julie Colley, Bal Shinder, Jayne Jones, Marisa Mills, Mandy Carnahan, Natalie Taylor, Kerenza Boulton, Julie Tregonning, Carly Brown, Gayle Clifford, Emily Archer, Mária Hamilton, Janette Curtis, Tracey Shewan, Sue Walsh, Karen L. Warner, Kimberley Netherton, McDonald Mupudzi, Bridget Gunson, Jane Gitahi, Denise Gocher, Sally Batham, Hilary Pateman, Senayon Desmennu, Jill Conder, Darren Clement, Susan Gallagher, Jacky Orpe, PuiChing Chan, Lynn Currie, L O’Donohoe, Metod Oblak, Lisa Morgan, Marie Quinn, Isobel Amey, Yolanda Baird, Donna Cotterill, Lourdes Cumlat, Louise de Winter, Sandra Greer, Katie Spurdle, Joanna Allison, Simon Dyer, Helen Sweeting, Jean Kordula, M. Eric Gershwin, Carl A. Anderson, Konstantinos N. Lazaridis, Pietro Invernizzi, Michael F. Seldin, Richard Sandford, Christopher I. Amos, Katherine A. Siminovitch
Bibliographic record
VenueNature Communications · 2015
Typereview
Languageen
FieldMedicine
TopicLiver Diseases and Immunity
Canadian institutionsUniversity of TorontoHôpital Saint-LucUniversity of CalgaryUniversité de MontréalUniversity of AlbertaLunenfeld-Tanenbaum Research InstituteMount Sinai Hospital
FundersNational Institute of Diabetes and Digestive and Kidney DiseasesMedical Research CouncilNational Cancer InstituteIsaac Newton TrustNational Institutes of HealthKing's College LondonNational Eye InstituteUniversity of PennsylvaniaNational Center for Advancing Translational SciencesWellcome TrustCanadian Institutes of Health ResearchNational Institute of General Medical SciencesNational Institute for Health and Care ResearchGordon and Betty Moore Foundation
KeywordsPrimary biliary cirrhosisGenotypingGenome-wide association studyBiliary cirrhosisBiologyMedicineImmunologyComputational biologyBioinformaticsGeneGeneticsAutoimmune diseaseAntibodyGenotypeSingle-nucleotide polymorphism
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.003
metaresearch head score (Gemma)0.003
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Meta-analysis · Consensus signal: none
GenreCandidate signal: Review · Consensus signal: Review
Teacher disagreement score0.004
Threshold uncertainty score0.014
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.004 | 0.004 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.113
GPT teacher head0.353
Teacher spread0.241 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designMeta-analysis
Domainnot available
GenreReview
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations310
Published2015
Admission routes2
Has abstractyes