TY - JOUR
T1 - GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
AU - NIHR BioResource
AU - Genomics England Research Consortium Collaborators
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 - 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 - Bueser, Teofila
AU - Carr-White, Gerald
AU - Koziell, Ania
AU - Simpson, Michael
AU - Traylor, Matthew
AU - Trembath, Richard
AU - Wood, Nicholas
AU - Brown, M. A.
AU - Hubbard, T. J.P.
AU - Thomas, E. R.A.
AU - Nicolaides, Kypros
AU - Williamson, Catherine
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
Y1 - 2022/12
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 - http://www.scopus.com/inward/record.url?scp=85136080115&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29931-z
DO - 10.1038/s41467-022-29931-z
M3 - Article
C2 - 35977952
AN - SCOPUS:85136080115
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4840
ER -