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

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.

Genetically predicted lipids mediate the association between intrahepatic cholestasis of pregnancy and cardiovascular disease

“…This study categorizes the potential mediator factors into two major groups, as follows: (1) Blood lipids: low-density lipoprotein [LDL], high-density lipoprotein [HDL], total cholesterol [TC], triglycerides [TG], apolipoprotein A [Apo-A], and apolipoprotein B [Apo-B]; (2) Liver function markers: alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyl transferase [γ-GGT], and bile acid. The GWAS summary-level data for ICP were derived from a study by Dixon PH et al through GWAS Catalog ( https://www.ebi.ac.uk/gwas/ ), which conducted GWAS and a meta-analysis across three studies on ICP, encompassing a total of 1,138 cases and 153,642 controls ( 23 ). The GWAS summary-level data about CVD, HTN, CAD, blood lipids and liver function markers used in this study was issued by the Integrative Epidemiology Unit (IEU) open GWAS project ( https://gwas.mrcieu.ac.uk/ ).…”

Genome-wide characterization of circulating metabolic biomarkers

“…ICP increases the risk of meconium staining of amniotic fluid, preterm delivery, fetal bradycardia, fetal distress and fetal loss 47 . The genetic background of ICP is poorly characterized with few published GWASs 7 , 48 and the metabolic effect of the ICP loci has not been characterized. Compared with results of a recent ICP GWAS that included data from meta-analysis of an earlier FinnGen release (data freeze 4) and two other cohorts 48 , associations at nine loci ( GCKR , ABCG8 , ABCB11 , ABCB1–ABCB4 , CYP7A1 , SERPINA1 , GAPDHS – TMEM147 , SULT2A1 and HNF4A ) were replicated here and three novel loci ( UGT8 , NUP153 and HKDC1 ) were additionally identified.…”

Genome-wide characterization of circulating metabolic biomarkers reveals substantial pleiotropy and novel disease pathways

“…ICP increases the risk of meconium staining of amniotic fluid, preterm delivery, fetal bradycardia, fetal distress, and fetal loss 41 . The genetic background of ICP is poorly characterized with few published GWASs 7,42 and the metabolic impact of the ICP-loci has not been characterized. Compared to results of a recent ICP GWAS that included data from meta-analysis of an earlier FinnGen release (Data Freeze 4) and two other cohorts 42 , associations at nine loci ( GCKR, ABCG8, ABCB11, ABCB1, CYP7A1, SERPINA1, GAPDHS / TMEM147, SULT2A1, HNF4A ) were replicated here and three novel loci ( UGT8, NUP153, HKDC1 ) were additionally identified.…”

“…The genetic background of ICP is poorly characterized with few published GWASs 7,42 and the metabolic impact of the ICP-loci has not been characterized. Compared to results of a recent ICP GWAS that included data from meta-analysis of an earlier FinnGen release (Data Freeze 4) and two other cohorts 42 , associations at nine loci ( GCKR, ABCG8, ABCB11, ABCB1, CYP7A1, SERPINA1, GAPDHS / TMEM147, SULT2A1, HNF4A ) were replicated here and three novel loci ( UGT8, NUP153, HKDC1 ) were additionally identified. A pathway analysis of the ICP-associated loci showed that biological processes related to bile acid, glucose, and lipid metabolism were enriched for ICP (Supplementary Table S9), consistent with the metabolic trait associations.…”