GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
Authors: 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 ,   NIHR BioResource, 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 , 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 , Vonk Noordegraaf Anton , 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 ,   Genomics England Research Consortium Collaborators, 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. , Williamson Catherine 
Published: August 2022

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.