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

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, Jennifer Donnelly, Sharon Cooley, Michael Geary, Kypros Nicolaides, Malin Thorsell, William M. Hague, Maria Cecilia Estiu, Hanns-Ulrich Marschall, Daniel P. Gale and Catherine Williamson ()
Additional contact information
Peter H. Dixon: King’s College London
Adam P. Levine: 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
Jenny Chambers: ICP Support
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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29931-z

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