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

Lookup NU author(s): Dr Tina Biss, Dr Paul Brennan, Professor Patrick Chinnery, Philip Griffiths, Professor Rita HorvathORCiD, Dr Sally Johnson, Dr Patrick Yu Wai Man

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Abstract

© 2022, The Author(s). 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.


Publication metadata

Author(s): Dixon PH, Levine AP, Cebola I, Chan MMY, Amin AS, Aich A, Mozere M, Maude H, Mitchell AL, Zhang J, Adlard J, Ahmed M, Aitman T, Alachkar H, Allsup D, Almeida-King J, Ancliff P, Antrobus R, Armstrong R, Arno G, Ashford S, Astle W, Attwood A, Babbs C, Bakchoul T, Bariana T, Barwell J, Bennett D, Bentley D, Bierzynska A, Biss T, Bleda M, Bogaard H, Bourne C, Boyce S, Bradley J, Breen G, Brennan P, Brewer C, Brown M, Browning M, Buchan R, Buckland M, Bueser T, Burns S, Burren O, Calleja P, Carr-White G, Carss K, Casey R, Caulfield M, Chambers J, Chambers J, Cheng F, Chinnery PF, Christian M, Church C, Brod NC, Coghlan G, Colby E, Cole T, Collins J, Collins P, Colombo C, Condliffe R, Cook S, Cook T, Cooper N, Corris P, Crisp-Hihn A, Curry N, Danesino C, Daniels M, Daugherty L, Davis J, Deevi SVV, Dent T, Dewhurst E, Dixon P, Downes K, Drazyk A, Drewe E, Dutt T, Edgar D, Edwards K, Egner W, Erber W, Erwood M, Evans G, Evans DG, Everington T, Eyries M, Favier R, Fletcher D, Fox J, Frary A, French C, Freson K, Frontini M, Gale D, Gall H, Geoghegan C, Gerighty T, Ghio S, Ghofrani H-A, Gibbs S, Gilmour K, Girerd B, Goddard S, Gomez K, Gordins P, Gosal D, Graf S, Grassi L, Greene D, Greenhalgh L, Greinacher A, Gresele P, Griffiths P, Grigoriadou S, Grocock R, Grozeva D, Hackett S, Hadinnapola C, Hague W, Haimel M, Hall M, Hanson H, Harkness K, Harper A, Harris C, Hart D, Hassan A, Hayman G, Henderson A, Hoffmann J, Horvath R, Houweling A, Howard L, Hu F, Hudson G, Hughes J, Huissoon A, Humbert M, Humphray S, Hunter S, Hurles M, Izatt L, James R, Johnson S, Jolles S, Jolley J, Jurkute N, Kasanicki M, Kazkaz H, Kazmi R, Kelleher P, Kiely D, Kingston N, Klima R, Kostadima M, Kovacs G, Koziell A, Kreuzhuber R, Kuijpers T, Kumar A, Kumararatne D, Kuria M, Laffa M, Lalloo F, Lamber M, Alle HL, Lawrie A, Layton M, Lentaigne C, Levine A, Linger R, Longhurst H, Louka E, Ross RMK, Madan B, Maher E, Maimaris J, Mangles S, Mapeta R, Marchbank K, Marks S, Markus HS, Marshall A, Martin J, Mathias M, Matthews E, Maxwell H, McAlinden P, McCarthy M, Meacham S, Mead A, Megy K, Mehta S, Michaelides M, Millar C, Moledina S, Montani D, Moor T, Morrell N, Muir K, Mumford A, Newnham M, O'Sullivan J, Obaji S, Okoli S, Olschewski A, Olschewski H, Ong KR, Ormondroy E, Ouwehan W, Papadi S, Park S-M, Parry D, Paterson J, Peacock A, Peden J, Peerlinck K, Penkett C, Pepke-Zaba J, Petersen R, Pyle A, Rankin S, Rao A, Raymond FL, Rayner-Matthew P, Rees C, Rendon A, Renton T, Rice A, Richardson S, Richter A, Roberts I, Roughley C, Roy N, Sadeghi-Alavijeh O, Saleem M, Samani N, Sanchis-Juan A, Sargur R, Satchell S, Savic S, Scelsi L, Schulman S, Scully M, Searle C, Seeger W, Sewell C, Seyres D, Shapiro S, Sharmardina O, Shtoyerman R, Sibson K, Side L, Simeoni I, Simpson M, Sivapalaratnam S, Skytte A-B, Smith K, Smith KGC, Snape K, Soubrier F, Staines S, Staples E, Stark H, Stephens J, Stirrups K, Stock S, Suntharalingam J, Swietlik E, Tait RC, Talks K, Tan R, Thaventhiran J, Themistocleous A, Thomas M, Thomson K, Thrasher A, Thys C, Tischkowitz M, Titterton C, Toh C-H, Toshner M, Traylor M, Treacy C, Trembath R, Tuna S, Turek W, Turro E, Vale T, Van Geet C, Van Zuydam N, Vazquez-Lopez M, von Ziegenweidt J, Noordegraaf AV, Waisfisz Q, Walker S, Ware J, Watkins H, Watt C, Webster A, Wei W, Welch S, Wessels J, Westbury S, Westwood J-P, Wharton J, Whitehorn D, Whitworth J, Wilkins MR, Wong E, Wood N, Wood Y, Woods G, Woodward E, Wort S, Worth A, Yates K, Yong P, Young T, Yu P, Yu-Wai-Man P, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Brown MA, Caulfield MJ, Chan GC, Fowler T, Giess A, Hamblin A, Henderson S, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Leigh SEA, Leong IUS, Lopez FJ, Maleady-Crowe F, McEntagart M, Minneci F, Moutsianas L, Mueller M, Murugaesu N, Need AC, O'Donovan P, Odhams CA, Patch C, Perez-Gil D, Pereira MB, Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL, Thomas ERA, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska K, Wood SM, Chambers J, Syngelaki A, Donnelly J, Cooley S, Geary M, Nicolaides K, Thorsell M, Hague WM, Estiu MC, Estiu MC, Marschall H-U, Gale DP, Williamson C

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 1

Online publication date: 17/08/2022

Acceptance date: 08/04/2022

ISSN (electronic): 2041-1723

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41467-022-29931-z

DOI: 10.1038/s41467-022-29931-z

PubMed id: 35977952


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