GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
Peter Dixon, Adam P. Levine, Inês Cebola, Melanie Chan, Aliya S. Amin, Anshul Aich, Monika Mozere, Hannah Maude, Alice Mitchell, Jun Zhang, NIHR BioResource, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David Allsup, J. P. Almeida, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Chris Babbs, Tamam Bakchoul, Tadbir K. Bariana, Julian Barwell, David Bennett, David Bentley, Agnieszka Bierżyńska, Tina Biss, Marta Bleda, Harm Jan Bogaard, Christian Bourne, Sara Boyce, John Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew A. Brown, Michael J. Browning, Rachel Buchan, Matthew Buckland, Teofila Bueser, Siobhan O. Burns, Oliver S. Burren, Paul Calleja, Gerald Carr‐White, Keren Carss, Ruth Casey, Mark J. Caulfield, John C. Chambers, Jennifer Chambers, Floria Cheng, Patrick F. Chinnery, Martin Christian, Colin Church, Naomi Clements Brod, Gerry Coghlan, Elizabeth Colby, Trevor Cole, Janine Collins, Peter Collins, Camilla Colombo, Robin Condliffe, Stuart A. Cook, Terry Cook, Nichola Cooper, Paul A. Corris, Abigail Crisp-Hihn, Nicola Curry, Cesare Danesino, Matthew J. Daniels, Louise C. Daugherty, John B. Davis, Sri V. V. Deevi, Timothy Dent, Eleanor Dewhurst, Peter Dixon, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Tina Dutt, David Edgar, Karen L. Edwards, William Egner, Wendy N. Erber, Marie Erwood, Maria C. Estiú, Gillian Evans, D. Gareth Evans, Tamara Everington, Mélanie Eyries, Rémi Favier, Debra Fletcher, James Fox, Amy Frary, Courtney E. French, Kathleen Freson
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.