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

• Published in: Nature communications 2022-08, Vol.13 (1), p.4840-4840, Article 4840
• Main Authors: Dixon, Peter H., Levine, Adam P., Cebola, Inês, Chan, Melanie M. Y., Amin, Aliya S., Aich, Anshul, Mozere, Monika, Maude, Hannah, Mitchell, Alice L., Zhang, Jun, Chambers, Jenny, Syngelaki, Argyro, Donnelly, Jennifer, Cooley, Sharon, Geary, Michael, Nicolaides, Kypros, Thorsell, Malin, Hague, William M., Estiu, Maria Cecilia, Marschall, Hanns-Ulrich, Gale, Daniel P., Williamson, Catherine
• Format: Article
• Language: English
• Subjects: 45; 45/43; 631/208/191/2018; 631/208/205/2138; 692/699/1503/1607; Bile acids; Bile Acids and Salts; Birth; Cholestasis; Cholestasis, Intrahepatic - genetics; Female; Gallbladder diseases; Genes; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study; Genomes; Humanities and Social Sciences; Humans; Infant, Newborn; Liver; Liver diseases; Meta-analysis; multidisciplinary; Mutation; Pregnancy; Pregnancy Complications - genetics; Premature Birth; Pruritus; Regulatory sequences; Science; Science (multidisciplinary); Stillbirth
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29931-z

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. Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.