GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Authors: Peter Dixon, Adam P. Levine, Inês Cebola, Melanie Chan, Aliya S. Amin, Anshul Aich, Monika Mozere, Hannah Maude, Alice Mitchell, Jun Zhang, NIHR BioResource, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David Allsup, J. P. Almeida, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Chris Babbs, Tamam Bakchoul, Tadbir K. Bariana, Julian Barwell, David Bennett, David Bentley, Agnieszka Bierżyńska, Tina Biss, Marta Bleda, Harm Jan Bogaard, Christian Bourne, Sara Boyce, John Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew A. Brown, Michael J. Browning, Rachel Buchan, Matthew Buckland, Teofila Bueser, Siobhan O. Burns, Oliver S. Burren, Paul Calleja, Gerald Carr‐White, Keren Carss, Ruth Casey, Mark J. Caulfield, John C. Chambers, Jennifer Chambers, Floria Cheng, Patrick F. Chinnery, Martin Christian, Colin Church, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor Cole, Janine Collins, Peter Collins, Camilla Colombo, Robin Condliffe, Stuart A. Cook, Terry Cook, Nichola Cooper, Paul A. Corris, Abigail Crisp-Hihn, Nicola Curry, Cesare Danesino, Matthew J. Daniels, Louise C. Daugherty, John B. Davis, Sri V. V. Deevi, Timothy Dent, Eleanor Dewhurst, Peter Dixon, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Tina Dutt, David Edgar, Karen L. Edwards, William Egner, Wendy N. Erber, Marie Erwood, Maria C. Estiú, Gillian Evans, D. Gareth Evans, Tamara Everington, Mélanie Eyries, Rémi Favier, Debra Fletcher, James Fox, Amy Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Daniel P. Gale, Henning Gall, Claire Geoghegan, Terry Gerighty, Stefano Ghio, Hossein-Ardeschir Ghofrani, Simon Gibbs, Kimberly Gilmour, Barbara Girerd, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Stefan Gräf, Luigi Grassi, Daniel Greene, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip G. Griffiths, Sofia Grigoriadou, Russell Grocock, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, William M. Hague, Matthias Haimel, Matthew D. Hall, Helen Hanson, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel P. Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Jonathan Hoffmann, Rita Horváth, Arjan C. Houweling, Luke Howard, Fengyuan Hu, Gavin Hudson, Joseph Hughes, Aarnoud Huissoon, Marc Humbert, Sean Humphray, Sarah Hunter, Matthew E. Hurles, Louise Izatt, Roger James, Sally Johnson, Stephen Jolles, Jennifer Jolley, Neringa Jurkutė, Mary Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, David G. Kiely, Nathalie Kingston, Robert Klima, Myrto Kostadima, Gábor Kovács, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju Kuria, Michael Laffa, Fiona Lalloo, Michele Lamber, Hana Lango Alle, Allan Lawrie, Mark Layton, Claire Lentaigne, Adam P. Levine, Rachel Linger, Hilary Longhurst, Eleni Louka, Robert MacKenzie Ross, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen D. Marks, Hugh S. Markus, Andrew Marshall, Jennifer M. Martin, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Stuart Meacham, Adam J. Mead, Karyn Mégy, Sarju Mehta, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, David Montani, Tony Moor, Nicholas W. Morrell, Keith W. Muir, Andrew Mumford, Michael Newnham, Jennifer O’Sullivan, Samya Obaji, Steven Okoli, Andrea Olschewski, Horst Olschewski, Kai Ren Ong, Elizabeth Ormondroy, Willem Ouwehan, Sofia Papadi, Soo‐Mi Park, David Parry, Joan Paterson, Andrew J. Peacock, John F. Peden, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke‐Żaba, R. Petersen, Angela Pyle, Stuart Rankin, Anupama Rao, F. Lucy Raymond, Paula Rayner-Matthew, Christine A. Rees, Augusto Rendon, Tara Renton, Andrew J. Rice, Sylvia Richardson, Alex Richter, Irene Roberts, Catherine Roughley, Noémi Roy, Omid Sadeghi‐Alavijeh, Moin A. Saleem, Nilesh J. Samani, Alba Sanchis-Juan, Ravishankar Sargur, Simon C. Satchell, Sinisa Savic, Laura Scelsi, Sol Schulman, Marie Scully, Claire Searle, Werner Seeger, Carrock Sewell, Denis Seyres, Susie Shapiro, Olga Sharmardina, Rakefet Chen‐Shtoyerman, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Suthesh Sivapalaratnam, Anne‐Bine Skytte, Katherine R. Smith, Kenneth G. C. Smith, Katie Snape, Florent Soubrier, Simon Staines, Emily Staples, Hannah Stark, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, Emilia M. Swietlik, R. Campbell Tait, Kate Talks, Rhea Tan, James Thaventhiran, Andreas C. Themistocleous, Moira Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng‐Hock Toh, Mark Toshner, Matthew Traylor, Carmen Treacy, Richard C. Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Tom Vale, Chris Van Geet, Natalie Van Zuydam, Marta Vazquez‐Lopez, Julie von Ziegenweidt, Anton Vonk Noordegraaf, Quintin Waisfisz, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher D. Watt, Andrew R. Webster, Wei Wei, Steven Welch, Julie Wessels, Sarah K. Westbury, John‐Paul Westwood, John Wharton, Deborah Whitehorn, James W. Whitworth, Martin R. Wilkins, Edwin Wong, Nicholas Wood, Yvette Wood, Geoff Woods, Emma R. Woodward, Stephen J. Wort, Austen Worth, Katherine P. Yates, Patrick Yong, Tim Young, Ping Yu, Patrick Yu‐Wai‐Man, John C. Ambrose, Prabhu Arumugam, R. Bevers, Marta Bleda, F. Boardman-Pretty, C. R. Boustred, Helen Brittain, Matthew A. Brown, Mark J. Caulfield, G. C. Chan, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim Hubbard, R. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, S. E. A. Leigh, I. U. S. Leong, Fabrice Lopez, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Christopher A. Odhams, Christine Patch, D. Perez-Gil, Mariana Buongermino Pereira, J. Pullinger, T. Rahim, Augusto Rendon, T. Rogers, K. Savage, K. Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ana Lisa Taylor Tavares, Ellen Thomas, Simon R. Thompson, Arianna Tucci, M. J. Welland, Eleanor Williams, Kate Witkowska, S. M. Wood, Jenny Chambers, Argyro Syngelaki, Jennifer Donnelly, Sharon Cooley, Michael Geary, K. H. Nicolaides, Malin Thorsell, William M. Hague, Maria C. Estiú, Hanns–Ulrich Marschall, Daniel P. Gale, Catherine Williamson - Nature Communications 2022 cited by 45

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.