GWAS Meta-analysis of Intrahepatic Cholestasis of Pregnancy Implicates Multiple Hepatic Genes and Regulatory Elements

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Aug 17

PMID 35977952

Authors

Peter H Dixon

Adam P Levine

Ines 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

Catherine Williamson

Affiliations

Soon will be listed here.

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.

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References

Ovadia C, Williamson C . Intrahepatic cholestasis of pregnancy: Recent advances. Clin Dermatol. 2016; 34(3):327-34. DOI: 10.1016/j.clindermatol.2016.02.004. View

Glantz A, Marschall H, Mattsson L . Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology. 2004; 40(2):467-74. DOI: 10.1002/hep.20336. View

Geenes V, Chappell L, Seed P, Steer P, Knight M, Williamson C . Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology. 2013; 59(4):1482-91. PMC: 4296226. DOI: 10.1002/hep.26617. View

Ovadia C, Seed P, Sklavounos A, Geenes V, Di Ilio C, Chambers J . Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet. 2019; 393(10174):899-909. PMC: 6396441. DOI: 10.1016/S0140-6736(18)31877-4. View

Reyes H, Baez M, Gonzalez M, Hernandez I, Palma J, Ribalta J . Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatol. 2000; 32(4):542-9. DOI: 10.1016/s0168-8278(00)80214-7. View

Abu-Hayyeh S, Papacleovoulou G, Lovgren-Sandblom A, Tahir M, Oduwole O, Jamaludin N . Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology. 2012; 57(2):716-26. PMC: 3592994. DOI: 10.1002/hep.26055. View

Abu-Hayyeh S, Ovadia C, Lieu T, Jensen D, Chambers J, Dixon P . Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology. 2015; 63(4):1287-98. PMC: 4869673. DOI: 10.1002/hep.28265. View

Turro E, Astle W, Megy K, Graf S, Greene D, Shamardina O . Whole-genome sequencing of patients with rare diseases in a national health system. Nature. 2020; 583(7814):96-102. PMC: 7610553. DOI: 10.1038/s41586-020-2434-2. View

Dixon P, Sambrotta M, Chambers J, Taylor-Harris P, Syngelaki A, Nicolaides K . An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep. 2017; 7(1):11823. PMC: 5603585. DOI: 10.1038/s41598-017-11626-x. View

10.

Dixon P, Wadsworth C, Chambers J, Donnelly J, Cooley S, Buckley R . A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol. 2013; 109(1):76-84. PMC: 3887577. DOI: 10.1038/ajg.2013.406. View

11.

Bull L, Hu D, Shah S, Temple L, Silva K, Huntsman S . Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping. PLoS One. 2015; 10(6):e0131211. PMC: 4488338. DOI: 10.1371/journal.pone.0131211. View

12.

Turnbull C, Scott R, Thomas E, Jones L, Murugaesu N, Pretty F . The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ. 2018; 361:k1687. DOI: 10.1136/bmj.k1687. View

13.

Zhou W, Nielsen J, Fritsche L, Dey R, Gabrielsen M, Wolford B . Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet. 2018; 50(9):1335-1341. PMC: 6119127. DOI: 10.1038/s41588-018-0184-y. View

14.

Willer C, Li Y, Abecasis G . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26(17):2190-1. PMC: 2922887. DOI: 10.1093/bioinformatics/btq340. View

15.

Yang J, Ferreira T, Morris A, Medland S, Madden P, Heath A . Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat Genet. 2012; 44(4):369-75, S1-3. PMC: 3593158. DOI: 10.1038/ng.2213. View

16.

Chang C, Chow C, Tellier L, Vattikuti S, Purcell S, Lee J . Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015; 4:7. PMC: 4342193. DOI: 10.1186/s13742-015-0047-8. View

17.

Kichaev G, Yang W, Lindstrom S, Hormozdiari F, Eskin E, Price A . Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 2014; 10(10):e1004722. PMC: 4214605. DOI: 10.1371/journal.pgen.1004722. View

18.

Davis C, Hitz B, Sloan C, Chan E, Davidson J, Gabdank I . The Encyclopedia of DNA elements (ENCODE): data portal update. Nucleic Acids Res. 2017; 46(D1):D794-D801. PMC: 5753278. DOI: 10.1093/nar/gkx1081. View

19.

Kircher M, Witten D, Jain P, ORoak B, Cooper G, Shendure J . A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014; 46(3):310-5. PMC: 3992975. DOI: 10.1038/ng.2892. View

20.

M Greene C, Marciniak S, Teckman J, Ferrarotti I, Brantly M, Lomas D . α1-Antitrypsin deficiency. Nat Rev Dis Primers. 2016; 2:16051. DOI: 10.1038/nrdp.2016.51. View