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

Dixon, Peter H., Levine, Adam P., Cebola, Inês, Chan, Melanie M. Y., Amin, Aliya S., Aich, Anshul, Mozere, Monika, Maude, Hannah, Mitchell, Alice L., Zhang, Jun, Adlard, Julian, Ahmed, Munaza, Aitman, Tim, Alachkar, Hana, Allsup, David, Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Astle, William, Attwood, Anthony, Babbs, Chris, Bakchoul, Tamam, Bariana, Tadbir, Barwell, Julian, Bennett, David, Bentley, David, Bierzynska, Agnieszka, Biss, Tina, Bleda, Marta, Bogaard, Harm, Bourne, Christian, Boyce, Sara, Bradley, John, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Michael, Buchan, Rachel, Buckland, Matthew, Bueser, Teofila, Burns, Siobhan, Burren, Oliver, Calleja, Paul, Carr-White, Gerald, Carss, Keren, Casey, Ruth, Caulfield, Mark, Chambers, John, Chambers, Jennifer, Cheng, Floria, Chinnery, Patrick F., Christian, Martin, Church, Colin, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor, Collins, Janine, Collins, Peter ORCID: https://orcid.org/0000-0002-6410-1324, Colombo, Camilla, Condliffe, Robin, Cook, Stuart, Cook, Terry, Cooper, Nichola, Corris, Paul, Crisp-Hihn, Abigail, Curry, Nicola, Danesino, Cesare, Daniels, Matthew, Daugherty, Louise, Davis, John, Deevi, Sri V. V., Dent, Timothy, Dewhurst, Eleanor, Dixon, Peter, Downes, Kate, Drazyk, Anna, Drewe, Elizabeth, Dutt, Tina, Edgar, David, Edwards, Karen, Egner, William, Erber, Wendy, Erwood, Marie, Estiu, Maria C., Evans, Gillian, Evans, Dafydd Gareth, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Fletcher, Debra, Fox, James, Frary, Amy, French, Courtney, Freson, Kathleen, Frontini, Mattia, Gale, Daniel, Gall, Henning, Geoghegan, Claire, Gerighty, Terry, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, Simon, Gilmour, Kimberley, Girerd, Barbara, Goddard, Sarah, Gomez, Keith, Gordins, Pavels, Gosal, David, Gräf, Stefan, Grassi, Luigi, Greene, Daniel, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell, Grozeva, Detelina, Hackett, Scott, Hadinnapola, Charaka, Hague, William, Haimel, Matthias, Hall, Matthew, Hanson, Helen, Harkness, Kirsty, Harper, Andrew, Harris, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Hoffmann, Jonathan, Horvath, Rita, Houweling, Arjan, Howard, Luke, Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud, Humbert, Marc, Humphray, Sean, Hunter, Sarah, Hurles, Matthew, Izatt, Louise, James, Roger, Johnson, Sally, Jolles, Stephen, Jolley, Jennifer, Jurkute, Neringa, Kasanicki, Mary, Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kiely, David, Kingston, Nathalie, Klima, Robert, Kostadima, Myrto, Kovacs, Gabor, Koziell, Ania, Kreuzhuber, Roman, Kuijpers, Taco, Kumar, Ajith, Kumararatne, Dinakantha, Kuria, Manju, Laffa, Michael, Lalloo, Fiona, Lamber, Michele, Alle, Hana Lango, Lawrie, Allan, Layton, Mark, Lentaigne, Claire, Levine, Adam, Linger, Rachel, Longhurst, Hilary, Louka, Eleni, Ross, Robert MacKenzie, Madan, Bella, Maher, Eamonn, Maimaris, Jesmeen, Mangles, Sarah, Mapeta, Rutendo, Marchbank, Kevin, Marks, Stephen, Markus, Hugh S., Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark, Meacham, Stuart, Mead, Adam, Megy, Karyn, Mehta, Sarju, Michaelides, Michel, Millar, Carolyn, Moledina, Shahin, Montani, David, Moor, Tony, Morrell, Nicholas, Muir, Keith, Mumford, Andrew, Newnham, Michael, O'Sullivan, Jennifer, Obaji, Samya, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Ormondroy, Elizabeth, Ouwehan, Willem, Papadi, Sofia, Park, Soo-Mi, Parry, David, Paterson, Joan, Peacock, Andrew, Peden, John, Peerlinck, Kathelijne, Penkett, Christopher, Pepke-Zaba, Joanna, Petersen, Romina, Pyle, Angela, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthew, Paula, Rees, Christine, Rendon, Augusto, Renton, Tara, Rice, Andrew, Richardson, Sylvia, Richter, Alex, Roberts, Irene, Roughley, Catherine, Roy, Noemi, Sadeghi-Alavijeh, Omid, Saleem, Moin, Samani, Nilesh, Sanchis-Juan, Alba, Sargur, Ravishankar, Satchell, Simon, Savic, Sinisa, Scelsi, Laura, Schulman, Sol, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, Carrock, Seyres, Denis, Shapiro, Susie, Sharmardina, Olga, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael, Sivapalaratnam, Suthesh, Skytte, Anne-Bine, Smith, Katherine, Smith, Kenneth G. C., Snape, Katie, Soubrier, Florent, Staines, Simon, Staples, Emily, Stark, Hannah, Stephens, Jonathan, Stirrups, Kathleen, Stock, Sophie, Suntharalingam, Jay, Swietlik, Emilia, Tait, R. Campbell, Talks, Kate, Tan, Rhea, Thaventhiran, James, Themistocleous, Andreas, Thomas, Moira, Thomson, Kate, Thrasher, Adrian, Thys, Chantal, Tischkowitz, Marc, Titterton, Catherine, Toh, Cheng-Hock, Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Trembath, Richard, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Vale, Tom, Van Geet, Chris, Van Zuydam, Natalie, Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Waisfisz, Quintin, Walker, Suellen, Ware, James, Watkins, Hugh, Watt, Christopher, Webster, Andrew, Wei, Wei, Welch, Steven, Wessels, Julie, Westbury, Sarah, Westwood, John-Paul, Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Wong, Edwin, Wood, Nicholas, Wood, Yvette, Woods, Geoff, Woodward, Emma, Wort, Stephen, Worth, Austen, Yates, Katherine, Yong, Patrick, Young, Tim, Yu, Ping, Yu-Wai-Man, Patrick, Ambrose, J. C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C. R., Brittain, H., Brown, M. A., Caulfield, M. J., Chan, G. C., Fowler, T., Giess, A., Hamblin, A., Henderson, S., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Leigh, S. E. A., Leong, I. U. S., Lopez, F. J., Maleady-Crowe, F., McEntagart, M., Minneci, F., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., O'Donovan, P., Odhams, C. A., Patch, C., Perez-Gil, D., Pereira, M. B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R. H., Siddiq, A., Sieghart, A., Smith, S. C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A. L., Thomas, E. R. A., Thompson, S. R., Tucci, A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Chambers, Jenny, Syngelaki, Argyro, Donnelly, Jennifer, Cooley, Sharon, Geary, Michael, Nicolaides, Kypros, Thorsell, Malin, Hague, William M., Estiu, Maria Cecilia, Marschall, Hanns-Ulrich, Gale, Daniel P. and Williamson, Catherine 2022. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements. Nature Communications 13 (1) , 4840. 10.1038/s41467-022-29931-z

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	2041-1723
Funders:	N/A
Date of First Compliant Deposit:	30 August 2022
Date of Acceptance:	8 April 2022
Last Modified:	23 May 2023 15:25
URI:	https://orca.cardiff.ac.uk/id/eprint/152068

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