Journal Article

Multiomics study of nonalcoholic fatty liver disease

Bjarnason, Ragnar G., Norddahl, Gudmundur L., Thorleifsson, Gudmar, Rognvaldsson, Solvi, Thorgeirsson, Gudmundur, Helgadottir, Anna, Melsted, Pall, Erikstrup, Christian, Nadauld, Lincoln, Sveinbjornsson, Gardar, Thorsteinsdottir, Unnur, Einarsson, Eythor, Rulifson, Ingrid C., Halldorsson, Gisli H., Pedersen, Ole Birger, Steinthorsdottir, Valgerdur, Arnar, David O., Gunnlaugsson, Gylfi, Olafsson, Isleifur, Knowlton, Kirk U., Rafnar, Thorunn, Bjornsson, Einar S., Eiriksdottir, Thjodbjorg, Ostrowski, Sisse Rye, Schwinn, Michael, Hindhede, Lotte, Holm, Hilma, Lund, Sigrun H., Bundgaard, Henning, Ferkingstad, Egil, Norland, Kristjan, Snaebjarnarson, Auðunn S., Baldvinsson, Magnus, Oskarsson, Gudjon R., Gudbjartsson, Daniel F., Olafsson, Sigurdur, Stefansson, Kari, Thorolfsdottir, Rosa B., Sigurdsson, Emil, Sulem, Patrick, Helgason, Hannes, Jonsdottir, Ingileif, Jonsson, Benedikt A., Ulfarsson, Magnus O., Hjorleifsson, Grimur, Jones, David

2022

Overview

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM , underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options. Genome-wide analyses identify loci associated with nonalcoholic fatty liver disease, including rare, protective loss-of-function variants in MTARC1 and GPAM . Plasma proteomic analyses provide insight into proteins involved in disease pathogenesis.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/23 / 45/43 / 59/57 / 631/208/205/2138 / 692/699/1503/1607 / Agriculture / Animal Genetics and Genomics / Biobanks / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer Research / Cirrhosis / Complications / Fatty liver / Gene expression / Gene Function / Genome-wide association studies / Genome-Wide Association Study / Genomes / Health problems / Hepatocellular carcinoma / Human Genetics / Humans / Lipid metabolism / Lipids / Liver / Liver - metabolism / Liver cancer / Liver cirrhosis / Liver Cirrhosis - genetics / Liver Cirrhosis - metabolism / Liver Cirrhosis - pathology / Liver diseases / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Magnetic resonance imaging / Non-alcoholic Fatty Liver Disease - genetics / Noninvasive evaluation / Pathogenesis / Plasma proteins / Proteins / Proteomics / Proton density (concentration) / Splicing / Therapeutic targets