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

NIHR BioResource; Genomics England Research Consortium Collaborators

doi:10.1038/s41467-022-29931-z

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

NIHR BioResource
, Genomics England Research Consortium Collaborators

King's College London
University College London
Imperial College London
Sun Yat-Sen University
Leeds Teaching Hospitals NHS Trust
NIHR Great Ormond Street Biomedical Research Centre, London, UK
University of Edinburgh
Northern Care Alliance NHS Group
Hull University Teaching Hospitals NHS Trust
European Molecular Biology Laboratory
University Hospitals Birmingham NHS Foundation Trust
University of Cambridge
Cancer Research UK
NIHR Cambridge Biomedical Research Centre
Cambridge University Hospitals NHS Foundation Trust
University of Oxford
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
University of Tübingen
Royal Free London NHS Foundation Trust, London, UK
Leicester Royal Infirmary
University of Leicester
Illumina Limited
University of Bristol
Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne, United Kingdom
Amsterdam UMC - Vrije Universiteit Amsterdam
Southampton General Hospital
Medical Research Council
Bethlem Royal Hospital, National Institute for Health Research Maudsley Biomedical Research Centre, and SLaM NHS Foundation Trust, National Autism Unit, London
Newcastle University
Newcastle upon Tyne Hospitals NHS Foundation Trust
Royal Devon & Exeter NHS Foundation Trust
Royal Brompton Hospital
Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
Clinical Genetics, Guy's and St. Thomas’ NHS Foundation Trust, London, United Kingdom
Department of Clinical Biochemistry, London, United Kingdom
Queen Mary University of London
Imperial College Healthcare NHS Trust
ICP Support
MRC Mitochondrial Biology Unit
Nottingham University Hospitals NHS Trust
Golden Jubilee National Hospital
West Midlands Regional Genetics Service, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
Department of Gastroenterology, The Royal London Hospital, Barts Health NHS Trust, London, UK
Adult Critical Care, University Hospital of Wales, Cardiff, UK
Royal Hallamshire Hospital
National Heart Centre Singapore
National University of Singapore
Oxford University Hospitals NHS Foundation Trust
University of Pavia
The Roald Dahl Haemostasis and Thrombosis Centre, The Royal Liverpool University Hospital, Liverpool, UK
Royal Victoria Hospital Belfast
Sheffield Teaching Hospitals NHS Foundation Trust
University of Western Australia
Ramón Sardá Mother’s and Children’s Hospital, Buenos Aires, Argentina
East Kent Hospitals University NHS Foundation Trust
St. Mary's Hospital
Salisbury NHS Foundation Trust
Sorbonne Université
Université Paris-Sud
Hôpital Armand Trousseau
KU Leuven
Universities of Giessen and Marburg Lung Center
IRCCS Fondazione Policlinico San Matteo - Pavia
Université Paris-Saclay
Assistance publique – Hôpitaux de Paris
INSERM U999, Hospital Marie Lannelongue, Le Plessis Robinson, France
University Hospitals of North Midlands NHS Trust
Liverpool Women's NHS Foundation Trust
University of Greifswald
University of Perugia
Barts Health NHS Foundation Trust, London, UK
Robinson Research Institute, Adelaide, Australia
Epsom and St. Helier University Hospitals NHS Trust
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Wellcome Sanger Institute
Cardiff & Vale University Health Board
University College London Hospitals, London, UK
Ludwig Boltzmann Institute
Medical University of Graz
St Thomas’ Hospital and King’s College London School of Medicine, London, UK
Department of Paediatric Nephrology, Evelina London Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, UK
University of Pennsylvania
University of Sheffield
Royal United Hospitals Bath NHS Foundation Trust
Haemophilia, Haemostasis and Thrombosis Centre, Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK
Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK
Department of Haematology, Manchester Royal Infirmary, Manchester, M13 9WL, UK;
Department of Paediatric Nephrology and National Institute for Health Research/Wellcome Trust Clinical Research Facility University of Manchester, Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Manchester, UK
National Hospital for Neurology and Neurosurgery, London, United Kingdom
Department of Paediatric Oncology, Royal Hospital for Children, Glasgow, Scotland, UK
University of Glasgow
National Institute for Health Research Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK
Royal Papworth Hospital NHS Foundation Trust
Chelsea and Westminster Hospital NHS Foundation Trust
Beth Israel Deaconess Medical Center
Northern Lincolnshire and Goole NHS Foundation Trust
Kaplan Medical Center Israel
Aarhus University
Adult Critical Care, St George’s University Hospitals NHS Foundation Trust and St George’s University of London, London, UK
Glasgow Royal Infirmary
Gartnavel General Hospital
Frimley Park Hospital, Surrey, United Kingdom
King's College Hospital, London
Royal College of Surgeons in Ireland
Karolinska Institutet
University of Gothenburg
NIHR Bioresource
Salford Royal NHS FoundationTrust
Castle Hill Hospital
Royal Free London NHS Foundation Trust
Maudsley Hospital
Royal Devon and Exeter Hospital
Royal Brompton and Harefield NHS Trust
Kings College London
King's College Hospital NHS Foundation Trust
Cambridge Biomedical Campus
Birmingham Women's and Children's NHS Foundation Trust
Royal London Hospital
University Hospital of Wales
Singapore Duke-NUS Graduate Medical School
Churchill Hospital
Liverpool University Hospitals NHS Foundation Trust
Ramón Sardá Mother’s and Children’s Hospital
Kent and Canterbury Hospital
Saint Mary’s Hospital
Salisbury District Hospital
University of Giessen and Marburg Lung Center
le Plessis Robinson
Hull Royal Infirmary
Barts Health NHS Trust
Heartlands Hospital
University of Adelaide
Addenbrooke's Hospital
Guy’s & St Thomas’ NHS Foundation Trust
Hampshire Hospitals NHS Foundation Trust
University of Manchester
Manchester Royal Infirmary
National Institute for Health and Care Research
NHS Greater Glasgow and Clyde
University Hospitals Bristol and Weston NHS Foundation Trust
Papworth Hospital
St George’s University Hospitals
VU Medical Center
Frimley Health NHS Foundation Trust

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	4840
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-29931-z
Publication status	Published - 1 Dec 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 2 Zero Hunger
SDG 3 Good Health and Well-being

Access to Document

10.1038/s41467-022-29931-z

Gwas-meta-analysis-of-intrahepatic-cholestasis-of-pregnancy-implicates-multiple-hepatic-genes-and-regulatory-elements.pdfFinal published version, 1.79 MBLicence: CC BY

Cite this

@article{5e722afe13fa4fefbbe46e21c206d8b9,

title = "GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements",

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.",

author = "Dixon, \{Peter H.\} and Levine, \{Adam P.\} and In{\^e}s Cebola and Chan, \{Melanie M. Y.\} and Amin, \{Aliya S.\} and Anshul Aich and Monika Mozere and Hannah Maude and Mitchell, \{Alice L.\} and Jun Zhang and Julian Adlard and Munaza Ahmed and Tim Aitman and Hana Alachkar and David Allsup and Jeff Almeida-King and Philip Ancliff and Richard Antrobus and Ruth Armstrong and Gavin Arno and \{NIHR BioResource\} and Sofie Ashford and William Astle and Anthony Attwood and Chris Babbs and Tamam Bakchoul and Tadbir Bariana and Julian Barwell and David Bennett and David Bentley and Agnieszka Bierzynska and Tina Biss and Marta Bleda and Harm Bogaard and Christian Bourne and Sara Boyce and John Bradley and Gerome Breen and Paul Brennan and Carole Brewer and Matthew Brown and Michael Browning and Rachel Buchan and Matthew Buckland and Teofila Bueser and Siobhan Burns and Oliver Burren and Paul Calleja and Gerald Carr-White and Keren Carss and Ruth Casey and \{Genomics England Research Consortium Collaborators\} and Mark Caulfield and John Chambers and Jennifer Chambers and Floria Cheng and Chinnery, \{Patrick F.\} and Martin Christian and Colin Church and Brod, \{Naomi Clements\} and Gerry Coghlan and Elizabeth Colby and Trevor Cole and Janine Collins and Peter Collins and Camilla Colombo and Robin Condliffe and Stuart Cook and Terry Cook and Nichola Cooper and Paul Corris and Abigail Crisp-Hihn and Nicola Curry and Cesare Danesino and Matthew Daniels and Louise Daugherty and John Davis and Deevi, \{Sri V. V.\} and Timothy Dent and Eleanor Dewhurst and Peter Dixon and Kate Downes and Anna Drazyk and Elizabeth Drewe and Tina Dutt and David Edgar and Karen Edwards and William Egner and Wendy Erber and Marie Erwood and Estiu, \{Maria C.\} and Gillian Evans and Evans, \{Dafydd Gareth\} and Tamara Everington and Eyries, \{M. lanie\} and Remi Favier and Debra Fletcher and James Fox and Amy Frary and Courtney French and Kathleen Freson and Mattia Frontini and Daniel Gale and Henning Gall and Claire Geoghegan and Terry Gerighty and Stefano Ghio and Hossein-Ardeschir Ghofrani and Simon Gibbs and Kimberley Gilmour and Barbara Girerd and Sarah Goddard and Keith Gomez and Pavels Gordins and David Gosal and Stefan Gr{\"a}f and Luigi Grassi and Daniel Greene and Lynn Greenhalgh and Andreas Greinacher and Paolo Gresele and Philip Griffiths and Sofia Grigoriadou and Russell Grocock and Detelina Grozeva and Scott Hackett and Charaka Hadinnapola and William Hague and Matthias Haimel and Matthew Hall and Helen Hanson and Kirsty Harkness and Andrew Harper and Claire Harris and Daniel Hart and Ahamad Hassan and Grant Hayman and Alex Henderson and Jonathan Hoffmann and Rita Horvath and Arjan Houweling and Luke Howard and Fengyuan Hu and Gavin Hudson and Joseph Hughes and Aarnoud Huissoon and Marc Humbert and Sean Humphray and Sarah Hunter and Matthew Hurles and Louise Izatt and Roger James and Sally Johnson and Stephen Jolles and Jennifer Jolley and Neringa Jurkute and Mary Kasanicki and Hanadi Kazkaz and Rashid Kazmi and Peter Kelleher and David Kiely and Nathalie Kingston and Robert Klima and Myrto Kostadima and Gabor Kovacs and Ania Koziell and Roman Kreuzhuber and Taco Kuijpers and Ajith Kumar and Dinakantha Kumararatne and Manju Kuria and Michael Laffa and Fiona Lalloo and Michele Lamber and Alle, \{Hana Lango\} and Allan Lawrie and Mark Layton and Claire Lentaigne and Adam Levine and Rachel Linger and Hilary Longhurst and Eleni Louka and Ross, \{Robert MacKenzie\} and Bella Madan and Eamonn Maher and Jesmeen Maimaris and Sarah Mangles and Rutendo Mapeta and Kevin Marchbank and Stephen Marks and Markus, \{Hugh S.\} and Andrew Marshall and Jennifer Martin and Mary Mathias and Emma Matthews and Heather Maxwell and Paul McAlinden and Mark McCarthy and Stuart Meacham and Adam Mead and Karyn Megy and Sarju Mehta and Michel Michaelides and Carolyn Millar and Shahin Moledina and David Montani and Tony Moor and Nicholas Morrell and Keith Muir and Andrew Mumford and Michael Newnham and Jennifer O{\textquoteright}Sullivan and Samya Obaji and Steven Okoli and Andrea Olschewski and Horst Olschewski and Ong, \{Kai Ren\} and Elizabeth Ormondroy and Willem Ouwehan and Sofia Papadi and Soo-Mi Park and David Parry and Joan Paterson and Andrew Peacock and John Peden and Kathelijne Peerlinck and Christopher Penkett and Joanna Pepke-Zaba and Romina Petersen and Angela Pyle and Stuart Rankin and Anupama Rao and Raymond, \{F. Lucy\} and Paula Rayner-Matthew and Christine Rees and Augusto Rendon and Tara Renton and Andrew Rice and Sylvia Richardson and Alex Richter and Irene Roberts and Catherine Roughley and Noemi Roy and Omid Sadeghi-Alavijeh and Moin Saleem and Nilesh Samani and Alba Sanchis-Juan and Ravishankar Sargur and Simon Satchell and Sinisa Savic and Laura Scelsi and Sol Schulman and Marie Scully and Claire Searle and Werner Seeger and Carrock Sewell and Denis Seyres and Susie Shapiro and Olga Sharmardina and Rakefet Shtoyerman and Keith Sibson and Lucy Side and Ilenia Simeoni and Michael Simpson and Suthesh Sivapalaratnam and Anne-Bine Skytte and Katherine Smith and Smith, \{Kenneth G. C.\} and Katie Snape and Florent Soubrier and Simon Staines and Emily Staples and Hannah Stark and Jonathan Stephens and Kathleen Stirrups and Sophie Stock and Jay Suntharalingam and Emilia Swietlik and Tait, \{R. Campbell\} and Kate Talks and Rhea Tan and James Thaventhiran and Andreas Themistocleous and Moira Thomas and Kate Thomson and Adrian Thrasher and Chantal Thys and Marc Tischkowitz and Catherine Titterton and Cheng-Hock Toh and Mark Toshner and Matthew Traylor and Carmen Treacy and Richard Trembath and Salih Tuna and Wojciech Turek and Ernest Turro and Tom Vale and \{van Geet\}, Chris and \{van Zuydam\}, Natalie and Marta Vazquez-Lopez and \{von Ziegenweidt\}, Julie and Noordegraaf, \{Anton Vonk\} and Quintin Waisfisz and Suellen Walker and James Ware and Hugh Watkins and Christopher Watt and Andrew Webster and Wei Wei and Steven Welch and Julie Wessels and Sarah Westbury and John-Paul Westwood and John Wharton and Deborah Whitehorn and James Whitworth and Wilkins, \{Martin R.\} and Edwin Wong and Nicholas Wood and Yvette Wood and Geoff Woods and Emma Woodward and Stephen Wort and Austen Worth and Katherine Yates and Patrick Yong and Tim Young and Ping Yu and Patrick Yu-Wai-Man and Ambrose, \{J. C.\} and P. Arumugam and R. Bevers and M. Bleda and F. Boardman-Pretty and Boustred, \{C. R.\} and H. Brittain and Brown, \{M. A.\} and Caulfield, \{M. J.\} and Chan, \{G. C.\} and T. Fowler and A. Giess and A. Hamblin and S. Henderson and Hubbard, \{T. J. P.\} and R. Jackson and Jones, \{L. J.\} and D. Kasperaviciute and M. Kayikci and A. Kousathanas and L. Lahnstein and Leigh, \{S. E. A.\} and Leong, \{I. U. S.\} and Lopez, \{F. J.\} and F. Maleady-Crowe and M. McEntagart and F. Minneci and L. Moutsianas and M. Mueller and N. Murugaesu and Need, \{A. C.\} and P. O{\textquoteright}Donovan and Odhams, \{C. A.\} and C. Patch and D. Perez-Gil and Pereira, \{M. B.\} and J. Pullinger and T. Rahim and A. Rendon and T. Rogers and K. Savage and K. Sawant and Scott, \{R. H.\} and A. Siddiq and A. Sieghart and Smith, \{S. C.\} and A. Sosinsky and A. Stuckey and M. Tanguy and \{Taylor Tavares\}, \{A. L.\} and Thomas, \{E. R. A.\} and Thompson, \{S. R.\} and A. Tucci and Welland, \{M. 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note = "Funding Information: We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource Centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. P.H.D. and C.W. are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy{\textquoteright}s and St Thomas{\textquoteright} Foundation Trust and King{\textquoteright}s College London. A.P.L. is supported by an NIHR Academic Clinical Lectureship. C.W. is funded by an NIHR Senior Investigator award. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or Department of Health and Social Care. I.C. is an Academy of Medical Sciences Springboard Fellow (SBF005\textbackslash{}1050). The Scheme is supported by the British Heart Foundation, Diabetes UK, the Global Challenges Research Fund, the Government Department for Business, Energy and Industrial Strategy and the Wellcome Trust. I.C. was also supported by the Foundation of National Institutes of Health (FNIH) and the Accelerated Medicines Partnerships Type 2 Diabetes (AMP T2D) initiative (RFP16) and by the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College Healthcare NHS Trust. We also thank the Imperial College London High-Performance Computing Service. MMYC is supported by a Kidney Research UK Clinical Training Fellowship. D.P.G. is supported by the St Peter{\textquoteright}s Trust. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on May 12, 2021. This research was also made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The authors gratefully acknowledge the participation of the patients and their families recruited to the 100,000 Genomes Project. We want to acknowledge the participants and investigators of the FinnGen study. Funding Information: We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource Centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. P.H.D. and C.W. are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy{\textquoteright}s and St Thomas{\textquoteright} Foundation Trust and King{\textquoteright}s College London. A.P.L. is supported by an NIHR Academic Clinical Lectureship. C.W. is funded by an NIHR Senior Investigator award. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or Department of Health and Social Care. I.C. is an Academy of Medical Sciences Springboard Fellow (SBF005\textbackslash{}1050). The Scheme is supported by the British Heart Foundation, Diabetes UK, the Global Challenges Research Fund, the Government Department for Business, Energy and Industrial Strategy and the Wellcome Trust. I.C. was also supported by the Foundation of National Institutes of Health (FNIH) and the Accelerated Medicines Partnerships Type 2 Diabetes (AMP T2D) initiative (RFP16) and by the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College Healthcare NHS Trust. We also thank the Imperial College London High-Performance Computing Service. MMYC is supported by a Kidney Research UK Clinical Training Fellowship. D.P.G. is supported by the St Peter{\textquoteright}s Trust. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on May 12, 2021. This research was also made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The authors gratefully acknowledge the participation of the patients and their families recruited to the 100,000 Genomes Project. We want to acknowledge the participants and investigators of the FinnGen study. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

day = "1",

doi = "10.1038/s41467-022-29931-z",

language = "English",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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T1 - GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

AU - Dixon, Peter H.

AU - Levine, Adam P.

AU - Cebola, Inês

AU - Chan, Melanie M. Y.

AU - Amin, Aliya S.

AU - Aich, Anshul

AU - Mozere, Monika

AU - Maude, Hannah

AU - Mitchell, Alice L.

AU - Zhang, Jun

AU - Adlard, Julian

AU - Ahmed, Munaza

AU - Aitman, Tim

AU - Alachkar, Hana

AU - Allsup, David

AU - Almeida-King, Jeff

AU - Ancliff, Philip

AU - Antrobus, Richard

AU - Armstrong, Ruth

AU - Arno, Gavin

AU - NIHR BioResource

AU - Ashford, Sofie

AU - Astle, William

AU - Attwood, Anthony

AU - Babbs, Chris

AU - Bakchoul, Tamam

AU - Bariana, Tadbir

AU - Barwell, Julian

AU - Bennett, David

AU - Bentley, David

AU - Bierzynska, Agnieszka

AU - Biss, Tina

AU - Bleda, Marta

AU - Bogaard, Harm

AU - Bourne, Christian

AU - Boyce, Sara

AU - Bradley, John

AU - Breen, Gerome

AU - Brennan, Paul

AU - Brewer, Carole

AU - Brown, Matthew

AU - Browning, Michael

AU - Buchan, Rachel

AU - Buckland, Matthew

AU - Bueser, Teofila

AU - Burns, Siobhan

AU - Burren, Oliver

AU - Calleja, Paul

AU - Carr-White, Gerald

AU - Carss, Keren

AU - Casey, Ruth

AU - Genomics England Research Consortium Collaborators

AU - Caulfield, Mark

AU - Chambers, John

AU - Chambers, Jennifer

AU - Cheng, Floria

AU - Chinnery, Patrick F.

AU - Christian, Martin

AU - Church, Colin

AU - Brod, Naomi Clements

AU - Coghlan, Gerry

AU - Colby, Elizabeth

AU - Cole, Trevor

AU - Collins, Janine

AU - Collins, Peter

AU - Colombo, Camilla

AU - Condliffe, Robin

AU - Cook, Stuart

AU - Cook, Terry

AU - Cooper, Nichola

AU - Corris, Paul

AU - Crisp-Hihn, Abigail

AU - Curry, Nicola

AU - Danesino, Cesare

AU - Daniels, Matthew

AU - Daugherty, Louise

AU - Davis, John

AU - Deevi, Sri V. V.

AU - Dent, Timothy

AU - Dewhurst, Eleanor

AU - Dixon, Peter

AU - Downes, Kate

AU - Drazyk, Anna

AU - Drewe, Elizabeth

AU - Dutt, Tina

AU - Edgar, David

AU - Edwards, Karen

AU - Egner, William

AU - Erber, Wendy

AU - Erwood, Marie

AU - Estiu, Maria C.

AU - Evans, Gillian

AU - Evans, Dafydd Gareth

AU - Everington, Tamara

AU - Eyries, M. lanie

AU - Favier, Remi

AU - Fletcher, Debra

AU - Fox, James

AU - Frary, Amy

AU - French, Courtney

AU - Freson, Kathleen

AU - Frontini, Mattia

AU - Gale, Daniel

AU - Gall, Henning

AU - Geoghegan, Claire

AU - Gerighty, Terry

AU - Ghio, Stefano

AU - Ghofrani, Hossein-Ardeschir

AU - Gibbs, Simon

AU - Gilmour, Kimberley

AU - Girerd, Barbara

AU - Goddard, Sarah

AU - Gomez, Keith

AU - Gordins, Pavels

AU - Gosal, David

AU - Gräf, Stefan

AU - Grassi, Luigi

AU - Greene, Daniel

AU - Greenhalgh, Lynn

AU - Greinacher, Andreas

AU - Gresele, Paolo

AU - Griffiths, Philip

AU - Grigoriadou, Sofia

AU - Grocock, Russell

AU - Grozeva, Detelina

AU - Hackett, Scott

AU - Hadinnapola, Charaka

AU - Hague, William

AU - Haimel, Matthias

AU - Hall, Matthew

AU - Hanson, Helen

AU - Harkness, Kirsty

AU - Harper, Andrew

AU - Harris, Claire

AU - Hart, Daniel

AU - Hassan, Ahamad

AU - Hayman, Grant

AU - Henderson, Alex

AU - Hoffmann, Jonathan

AU - Horvath, Rita

AU - Houweling, Arjan

AU - Howard, Luke

AU - Hu, Fengyuan

AU - Hudson, Gavin

AU - Hughes, Joseph

AU - Huissoon, Aarnoud

AU - Humbert, Marc

AU - Humphray, Sean

AU - Hunter, Sarah

AU - Hurles, Matthew

AU - Izatt, Louise

AU - James, Roger

AU - Johnson, Sally

AU - Jolles, Stephen

AU - Jolley, Jennifer

AU - Jurkute, Neringa

AU - Kasanicki, Mary

AU - Kazkaz, Hanadi

AU - Kazmi, Rashid

AU - Kelleher, Peter

AU - Kiely, David

AU - Kingston, Nathalie

AU - Klima, Robert

AU - Kostadima, Myrto

AU - Kovacs, Gabor

AU - Koziell, Ania

AU - Kreuzhuber, Roman

AU - Kuijpers, Taco

AU - Kumar, Ajith

AU - Kumararatne, Dinakantha

AU - Kuria, Manju

AU - Laffa, Michael

AU - Lalloo, Fiona

AU - Lamber, Michele

AU - Alle, Hana Lango

AU - Lawrie, Allan

AU - Layton, Mark

AU - Lentaigne, Claire

AU - Levine, Adam

AU - Linger, Rachel

AU - Longhurst, Hilary

AU - Louka, Eleni

AU - Ross, Robert MacKenzie

AU - Madan, Bella

AU - Maher, Eamonn

AU - Maimaris, Jesmeen

AU - Mangles, Sarah

AU - Mapeta, Rutendo

AU - Marchbank, Kevin

AU - Marks, Stephen

AU - Markus, Hugh S.

AU - Marshall, Andrew

AU - Martin, Jennifer

AU - Mathias, Mary

AU - Matthews, Emma

AU - Maxwell, Heather

AU - McAlinden, Paul

AU - McCarthy, Mark

AU - Meacham, Stuart

AU - Mead, Adam

AU - Megy, Karyn

AU - Mehta, Sarju

AU - Michaelides, Michel

AU - Millar, Carolyn

AU - Moledina, Shahin

AU - Montani, David

AU - Moor, Tony

AU - Morrell, Nicholas

AU - Muir, Keith

AU - Mumford, Andrew

AU - Newnham, Michael

AU - O’Sullivan, Jennifer

AU - Obaji, Samya

AU - Okoli, Steven

AU - Olschewski, Andrea

AU - Olschewski, Horst

AU - Ong, Kai Ren

AU - Ormondroy, Elizabeth

AU - Ouwehan, Willem

AU - Papadi, Sofia

AU - Park, Soo-Mi

AU - Parry, David

AU - Paterson, Joan

AU - Peacock, Andrew

AU - Peden, John

AU - Peerlinck, Kathelijne

AU - Penkett, Christopher

AU - Pepke-Zaba, Joanna

AU - Petersen, Romina

AU - Pyle, Angela

AU - Rankin, Stuart

AU - Rao, Anupama

AU - Raymond, F. Lucy

AU - Rayner-Matthew, Paula

AU - Rees, Christine

AU - Rendon, Augusto

AU - Renton, Tara

AU - Rice, Andrew

AU - Richardson, Sylvia

AU - Richter, Alex

AU - Roberts, Irene

AU - Roughley, Catherine

AU - Roy, Noemi

AU - Sadeghi-Alavijeh, Omid

AU - Saleem, Moin

AU - Samani, Nilesh

AU - Sanchis-Juan, Alba

AU - Sargur, Ravishankar

AU - Satchell, Simon

AU - Savic, Sinisa

AU - Scelsi, Laura

AU - Schulman, Sol

AU - Scully, Marie

AU - Searle, Claire

AU - Seeger, Werner

AU - Sewell, Carrock

AU - Seyres, Denis

AU - Shapiro, Susie

AU - Sharmardina, Olga

AU - Shtoyerman, Rakefet

AU - Sibson, Keith

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N1 - Funding Information: We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource Centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. P.H.D. and C.W. are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust and King’s College London. A.P.L. is supported by an NIHR Academic Clinical Lectureship. C.W. is funded by an NIHR Senior Investigator award. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or Department of Health and Social Care. I.C. is an Academy of Medical Sciences Springboard Fellow (SBF005\1050). The Scheme is supported by the British Heart Foundation, Diabetes UK, the Global Challenges Research Fund, the Government Department for Business, Energy and Industrial Strategy and the Wellcome Trust. I.C. was also supported by the Foundation of National Institutes of Health (FNIH) and the Accelerated Medicines Partnerships Type 2 Diabetes (AMP T2D) initiative (RFP16) and by the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College Healthcare NHS Trust. We also thank the Imperial College London High-Performance Computing Service. MMYC is supported by a Kidney Research UK Clinical Training Fellowship. D.P.G. is supported by the St Peter’s Trust. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on May 12, 2021. This research was also made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The authors gratefully acknowledge the participation of the patients and their families recruited to the 100,000 Genomes Project. We want to acknowledge the participants and investigators of the FinnGen study. Funding Information: We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource Centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. P.H.D. and C.W. are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust and King’s College London. A.P.L. is supported by an NIHR Academic Clinical Lectureship. C.W. is funded by an NIHR Senior Investigator award. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or Department of Health and Social Care. I.C. is an Academy of Medical Sciences Springboard Fellow (SBF005\1050). The Scheme is supported by the British Heart Foundation, Diabetes UK, the Global Challenges Research Fund, the Government Department for Business, Energy and Industrial Strategy and the Wellcome Trust. I.C. was also supported by the Foundation of National Institutes of Health (FNIH) and the Accelerated Medicines Partnerships Type 2 Diabetes (AMP T2D) initiative (RFP16) and by the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College Healthcare NHS Trust. We also thank the Imperial College London High-Performance Computing Service. MMYC is supported by a Kidney Research UK Clinical Training Fellowship. D.P.G. is supported by the St Peter’s Trust. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on May 12, 2021. This research was also made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The authors gratefully acknowledge the participation of the patients and their families recruited to the 100,000 Genomes Project. We want to acknowledge the participants and investigators of the FinnGen study. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85136080115

U2 - 10.1038/s41467-022-29931-z

DO - 10.1038/s41467-022-29931-z

M3 - Article

C2 - 35977952

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4840

ER -

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

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