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

Author

Listed:
  • Peter H. Dixon

    (King’s College London)

  • Adam P. Levine

    (University College London
    University College London)

  • Inês Cebola

    (Imperial College London)

  • Melanie M. Y. Chan

    (University College London)

  • Aliya S. Amin

    (King’s College London)

  • Anshul Aich

    (University College London)

  • Monika Mozere

    (University College London)

  • Hannah Maude

    (Imperial College London)

  • Alice L. Mitchell

    (King’s College London)

  • Jun Zhang

    (University College London
    Third Affiliated Hospital of Sun Yat-Sen University)

  • Jenny Chambers

    (ICP Support
    Imperial College London)

  • Argyro Syngelaki

    (King’s College Hospital)

  • Jennifer Donnelly

    (The Rotunda Hospital)

  • Sharon Cooley

    (The Rotunda Hospital)

  • Michael Geary

    (The Rotunda Hospital)

  • Kypros Nicolaides

    (King’s College Hospital)

  • Malin Thorsell

    (Danderyd Hospital)

  • William M. Hague

    (The University of Adelaide)

  • Maria Cecilia Estiu

    (Ramón Sardá Mother’s and Children’s Hospital)

  • Hanns-Ulrich Marschall

    (University of Gothenburg)

  • Daniel P. Gale

    (University College London)

  • Catherine Williamson

    (King’s College London)

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.

Suggested Citation

  • Peter H. Dixon & Adam P. Levine & Inês Cebola & Melanie M. Y. Chan & Aliya S. Amin & Anshul Aich & Monika Mozere & Hannah Maude & Alice L. Mitchell & Jun Zhang & Jenny Chambers & Argyro Syngelaki & Je, 2022. "GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29931-z
    DOI: 10.1038/s41467-022-29931-z
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    References listed on IDEAS

    as
    1. Luke Jostins & Adam P Levine & Jeffrey C Barrett, 2013. "Using Genetic Prediction from Known Complex Disease Loci to Guide the Design of Next-Generation Sequencing Experiments," PLOS ONE, Public Library of Science, vol. 8(10), pages 1-7, October.
    2. Danny Leung & Inkyung Jung & Nisha Rajagopal & Anthony Schmitt & Siddarth Selvaraj & Ah Young Lee & Chia-An Yen & Shin Lin & Yiing Lin & Yunjiang Qiu & Wei Xie & Feng Yue & Manoj Hariharan & Pradipta , 2015. "Integrative analysis of haplotype-resolved epigenomes across human tissues," Nature, Nature, vol. 518(7539), pages 350-354, February.
    3. Jesse R. Dixon & Siddarth Selvaraj & Feng Yue & Audrey Kim & Yan Li & Yin Shen & Ming Hu & Jun S. Liu & Bing Ren, 2012. "Topological domains in mammalian genomes identified by analysis of chromatin interactions," Nature, Nature, vol. 485(7398), pages 376-380, May.
    4. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    5. Tanya M. Teslovich & Kiran Musunuru & Albert V. Smith & Andrew C. Edmondson & Ioannis M. Stylianou & Masahiro Koseki & James P. Pirruccello & Samuli Ripatti & Daniel I. Chasman & Cristen J. Willer & C, 2010. "Biological, clinical and population relevance of 95 loci for blood lipids," Nature, Nature, vol. 466(7307), pages 707-713, August.
    6. Egil Ferkingstad & Asmundur Oddsson & Solveig Gretarsdottir & Stefania Benonisdottir & Gudmar Thorleifsson & Aimee M. Deaton & Stefan Jonsson & Olafur A. Stefansson & Gudmundur L. Norddahl & Florian Z, 2018. "Genome-wide association meta-analysis yields 20 loci associated with gallstone disease," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    7. Saskia Heybrock & Kristiina Kanerva & Ying Meng & Chris Ing & Anna Liang & Zi-Jian Xiong & Xialian Weng & Young Ah Kim & Richard Collins & William Trimble & Régis Pomès & Gilbert G. Privé & Wim Annaer, 2019. "Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    8. Kyoko Watanabe & Erdogan Taskesen & Arjen Bochoven & Danielle Posthuma, 2017. "Functional mapping and annotation of genetic associations with FUMA," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    9. Ernest Turro & William J. Astle & Karyn Megy & Stefan Gräf & Daniel Greene & Olga Shamardina & Hana Lango Allen & Alba Sanchis-Juan & Mattia Frontini & Chantal Thys & Jonathan Stephens & Rutendo Mapet, 2020. "Whole-genome sequencing of patients with rare diseases in a national health system," Nature, Nature, vol. 583(7814), pages 96-102, July.
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