Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.
Jonas GhouseGardar SveinbjörnssonMarijana VujkovicAnne-Sofie SeidelinHelene Gellert-KristensenGustav AhlbergVinicius TraganteSøren Albertsen RandJoseph BrancaleSilvia VilarinhoPia Rengtved LundegaardErik SørensenChristian ErikstrupMie Topholm BruunBitten Aagaard JensenSoren BrunakKarina BanasikHenrik Ullumnull nullNiek VerweijLuca A LottaAris Barasnull nullTooraj MirshahiDavid J Careynull nullnull nullDavid E KaplanJulie A LynchTimothy MorganTae-Hwi Schwantes-AnDaniel R DochtermannSaiju PyarajanPhilip S Tsaonull nullTriin LaiskReedik MägiJulia KozlitinaAnne Tybjærg-HansenDavid JonesKirk U KnowltonLincoln NadauldEgil FerkingstadEinar S BjörnssonMagnus O UlfarssonÁrni SturlusonPatrick SulemOle Birger Vesterager PedersenSisse Rye OstrowskiDaníel F GuðbjartssonKári StefánssonMorten Salling OlesenKyong-Mi ChangHilma HólmHenning BundgaardStefan StenderPublished in: Nature genetics (2024)
We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.