Multiomics study of nonalcoholic fatty liver disease
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Published:2022-10-24
Issue:11
Volume:54
Page:1652-1663
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Sveinbjornsson GardarORCID, Ulfarsson Magnus O., Thorolfsdottir Rosa B., Jonsson Benedikt A., Einarsson Eythor, Gunnlaugsson Gylfi, Rognvaldsson Solvi, Arnar David O., Baldvinsson Magnus, Bjarnason Ragnar G., Eiriksdottir ThjodbjorgORCID, Erikstrup ChristianORCID, Ferkingstad Egil, Halldorsson Gisli H., Helgason Hannes, Helgadottir AnnaORCID, Hindhede LotteORCID, Hjorleifsson GrimurORCID, Jones David, Knowlton Kirk U., Lund Sigrun H.ORCID, Melsted Pall, Norland Kristjan, Olafsson Isleifur, Olafsson Sigurdur, Oskarsson Gudjon R.ORCID, Ostrowski Sisse RyeORCID, Pedersen Ole BirgerORCID, Snaebjarnarson Auðunn S.ORCID, Sigurdsson Emil, Steinthorsdottir ValgerdurORCID, Schwinn Michael, Thorgeirsson Gudmundur, Thorleifsson GudmarORCID, Jonsdottir IngileifORCID, Bundgaard Henning, Nadauld Lincoln, Bjornsson Einar S., Rulifson Ingrid C., Rafnar ThorunnORCID, Norddahl Gudmundur L., Thorsteinsdottir Unnur, Sulem Patrick, Gudbjartsson Daniel F., Holm HilmaORCID, Stefansson KariORCID,
Abstract
AbstractNonalcoholic 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.
Publisher
Springer Science and Business Media LLC
Reference100 articles.
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