Genome-wide meta-analysis identifies genetic drivers of bile acid metabolism in intrahepatic cholestasis of pregnancy.
Tyrmi JS., Karjalainen J., Venkatesh SS., Benoit-Pilven C., Lemmelä SM., Brunak S., Aagaard B., Bruun MT., Erikstrup C., Ullum H., Pedersen OB., Banasik K., Sørensen E., Mikkelsen C., Schwinn M., Sturluson A., Ostrowski SR., FinnGen ., Estonian Biobank research team ., DBDS Genomic Consortium ., Kettunen J., Nielsen HS., Nyegaard M., Westergaard D., Rafnar T., Sulem P., Stefansson K., Palta P., Laisk T., Tukiainen T., Lindgren CM., Daly M., Havulinna AS., Laivuori HM.
Intrahepatic cholestasis of pregnancy, which affects 0.2-2% of pregnancies, is characterized by pruritus, increased aminotransferase activity and elevated serum bile acids. Previous studies have implicated liver-enriched genes in intrahepatic cholestasis of pregnancy. We conducted a meta-analysis of intrahepatic cholestasis of pregnancy genome-wide association studies in the FinnGen study, deCODE, Estonian Biobank, the Danish Blood Donor Study and Copenhagen Hospital Biobank with 4,738 women with prior ICP and 436,834 female controls. The analysis found 26 genome-wide significant associations of which 10 were novel. Genes in the associated loci were prioritized using lead SNP expression quantitative trait loci associations and colocalization analysis to assess potential causality. The associated loci implicate bile acid synthesis, LDL cholesterol, and lipid metabolism. Additionally, comorbidity, genetic correlation and polygenic risk score analyses further indicated a link between intrahepatic cholestasis of pregnancy and pancreatitis, suggesting shared genetic underpinnings.