Multiomics study of nonalcoholic fatty liver disease

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

doi:10.1038/s41588-022-01199-5

Multiomics study of nonalcoholic fatty liver disease

Gardar Sveinbjornsson^*, Magnus O Ulfarsson, Rosa B Thorolfsdottir, Benedikt A Jonsson, Eythor Einarsson, Gylfi Gunnlaugsson, Solvi Rognvaldsson, David O Arnar, Magnus Baldvinsson, Ragnar G Bjarnason, Thjodbjorg Eiriksdottir, Christian Erikstrup, Egil Ferkingstad, Gisli H Halldorsson, Hannes Helgason, Anna Helgadottir, Lotte Hindhede, Grimur Hjorleifsson, David Jones, Kirk U KnowltonSigrun H Lund, Pall Melsted, Kristjan Norland, Isleifur Olafsson, Sigurdur Olafsson, Gudjon R Oskarsson, Sisse Rye Ostrowski, Ole Birger Pedersen, Auðunn S Snaebjarnarson, Emil Sigurdsson, Valgerdur Steinthorsdottir, Michael Schwinn, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Ingileif Jonsdottir, Henning Bundgaard, Lincoln Nadauld, Einar S Bjornsson, Ingrid C Rulifson, Thorunn Rafnar, Gudmundur L Norddahl, Unnur Thorsteinsdottir, Patrick Sulem, Daniel F Gudbjartsson, Hilma Holm, Kari Stefansson^*, DBDS Genomic Consortium, Maria Didriksen (Medlem af forfattergruppering), Thomas Folkmann Hansen (Medlem af forfattergruppering), Poul Jørgen Jennum (Medlem af forfattergruppering), Pär Ingemar Johansson (Medlem af forfattergruppering), Sisse Rye Ostrowski (Medlem af forfattergruppering), Erik Sørensen (Medlem af forfattergruppering), Henrik Ullum (Medlem af forfattergruppering), DBDS Genomic Consortium , Christian Erikstrup (Medlem af forfattergruppering), Ole Birger Pedersen (Medlem af forfattergruppering), Unnur Thorsteinsdottir (Medlem af forfattergruppering), Daniel F Gudbjartsson (Medlem af forfattergruppering), Hilma Holm (Medlem af forfattergruppering), Kari Stefánsson (Medlem af forfattergruppering)

^*Corresponding author af dette arbejde

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	54
Udgave nummer	11
Sider (fra-til)	1652-1663
Antal sider	12
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-022-01199-5
Status	Udgivet - nov. 2022

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10.1038/s41588-022-01199-5

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Sveinbjornsson, G., Ulfarsson, M. O., Thorolfsdottir, R. B., Jonsson, B. A., Einarsson, E., Gunnlaugsson, G., Rognvaldsson, S., Arnar, D. O., Baldvinsson, M., Bjarnason, R. G., Eiriksdottir, T., Erikstrup, C., Ferkingstad, E., Halldorsson, G. H., Helgason, H., Helgadottir, A., Hindhede, L., Hjorleifsson, G., Jones, D., ... Stefánsson, K. (2022). Multiomics study of nonalcoholic fatty liver disease. Nature Genetics, 54(11), 1652-1663. https://doi.org/10.1038/s41588-022-01199-5

Sveinbjornsson, G, Ulfarsson, MO, Thorolfsdottir, RB, Jonsson, BA, Einarsson, E, Gunnlaugsson, G, Rognvaldsson, S, Arnar, DO, Baldvinsson, M, Bjarnason, RG, Eiriksdottir, T, Erikstrup, C, Ferkingstad, E, Halldorsson, GH, Helgason, H, Helgadottir, A, Hindhede, L, Hjorleifsson, G, Jones, D, Knowlton, KU, Lund, SH, Melsted, P, Norland, K, Olafsson, I, Olafsson, S, Oskarsson, GR, Ostrowski, SR, Pedersen, OB, Snaebjarnarson, AS, Sigurdsson, E, Steinthorsdottir, V, Schwinn, M, Thorgeirsson, G, Thorleifsson, G, Jonsdottir, I, Bundgaard, H, Nadauld, L, Bjornsson, ES, Rulifson, IC, Rafnar, T, Norddahl, GL, Thorsteinsdottir, U, Sulem, P, Gudbjartsson, DF, Holm, H, Stefansson, K, DBDS Genomic Consortium, Didriksen, M , Hansen, TF , Jennum, PJ , Johansson, PI , Ostrowski, SR , Sørensen, E, Ullum, H, DBDS Genomic Consortium , Erikstrup, C, Pedersen, OB, Thorsteinsdottir, U, Gudbjartsson, DF, Holm, H & Stefánsson, K 2022, 'Multiomics study of nonalcoholic fatty liver disease', Nature Genetics, bind 54, nr. 11, s. 1652-1663. https://doi.org/10.1038/s41588-022-01199-5

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title = "Multiomics study of nonalcoholic fatty liver disease",

abstract = "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.",

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author = "Gardar Sveinbjornsson and Ulfarsson, {Magnus O} and Thorolfsdottir, {Rosa B} and Jonsson, {Benedikt A} and Eythor Einarsson and Gylfi Gunnlaugsson and Solvi Rognvaldsson and Arnar, {David O} and Magnus Baldvinsson and Bjarnason, {Ragnar G} and Thjodbjorg Eiriksdottir and Christian Erikstrup and Egil Ferkingstad and Halldorsson, {Gisli H} and Hannes Helgason and Anna Helgadottir and Lotte Hindhede and Grimur Hjorleifsson and David Jones and Knowlton, {Kirk U} and Lund, {Sigrun H} and Pall Melsted and Kristjan Norland and Isleifur Olafsson and Sigurdur Olafsson and Oskarsson, {Gudjon R} and Ostrowski, {Sisse Rye} and Pedersen, {Ole Birger} and Snaebjarnarson, {Au{\dh}unn S} and Emil Sigurdsson and Valgerdur Steinthorsdottir and Michael Schwinn and Gudmundur Thorgeirsson and Gudmar Thorleifsson and Ingileif Jonsdottir and Henning Bundgaard and Lincoln Nadauld and Bjornsson, {Einar S} and Rulifson, {Ingrid C} and Thorunn Rafnar and Norddahl, {Gudmundur L} and Unnur Thorsteinsdottir and Patrick Sulem and Gudbjartsson, {Daniel F} and Hilma Holm and Kari Stefansson and {DBDS Genomic Consortium} and Maria Didriksen and Hansen, {Thomas Folkmann} and Jennum, {Poul J{\o}rgen} and Johansson, {P{\"a}r Ingemar} and Ostrowski, {Sisse Rye} and Erik S{\o}rensen and Henrik Ullum and {DBDS Genomic Consortium} and Christian Erikstrup and Pedersen, {Ole Birger} and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F} and Hilma Holm and Kari Stef{\'a}nsson",

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year = "2022",

month = nov,

doi = "10.1038/s41588-022-01199-5",

language = "English",

volume = "54",

pages = "1652--1663",

journal = "Nature Genetics",

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T1 - Multiomics study of nonalcoholic fatty liver disease

AU - Sveinbjornsson, Gardar

AU - Ulfarsson, Magnus O

AU - Thorolfsdottir, Rosa B

AU - Jonsson, Benedikt A

AU - Einarsson, Eythor

AU - Gunnlaugsson, Gylfi

AU - Rognvaldsson, Solvi

AU - Arnar, David O

AU - Baldvinsson, Magnus

AU - Bjarnason, Ragnar G

AU - Eiriksdottir, Thjodbjorg

AU - Erikstrup, Christian

AU - Ferkingstad, Egil

AU - Halldorsson, Gisli H

AU - Helgason, Hannes

AU - Helgadottir, Anna

AU - Hindhede, Lotte

AU - Hjorleifsson, Grimur

AU - Jones, David

AU - Knowlton, Kirk U

AU - Lund, Sigrun H

AU - Melsted, Pall

AU - Norland, Kristjan

AU - Olafsson, Isleifur

AU - Olafsson, Sigurdur

AU - Oskarsson, Gudjon R

AU - Ostrowski, Sisse Rye

AU - Pedersen, Ole Birger

AU - Snaebjarnarson, Auðunn S

AU - Sigurdsson, Emil

AU - Steinthorsdottir, Valgerdur

AU - Schwinn, Michael

AU - Thorgeirsson, Gudmundur

AU - Thorleifsson, Gudmar

AU - Jonsdottir, Ingileif

AU - Bundgaard, Henning

AU - Nadauld, Lincoln

AU - Bjornsson, Einar S

AU - Rulifson, Ingrid C

AU - Rafnar, Thorunn

AU - Norddahl, Gudmundur L

AU - Thorsteinsdottir, Unnur

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F

AU - Holm, Hilma

AU - Stefansson, Kari

AU - DBDS Genomic Consortium

A2 - Didriksen, Maria

A2 - Hansen, Thomas Folkmann

A2 - Jennum, Poul Jørgen

A2 - Johansson, Pär Ingemar

A2 - Ostrowski, Sisse Rye

A2 - Sørensen, Erik

A2 - Ullum, Henrik

A2 - Erikstrup, Christian

A2 - Pedersen, Ole Birger

A2 - Thorsteinsdottir, Unnur

A2 - Gudbjartsson, Daniel F

A2 - Holm, Hilma

A2 - Stefánsson, Kari

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

KW - Genome-Wide Association Study

KW - Humans

KW - Liver Cirrhosis/genetics

KW - Liver Neoplasms/genetics

KW - Liver/metabolism

KW - Non-alcoholic Fatty Liver Disease/genetics

KW - Proteomics

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U2 - 10.1038/s41588-022-01199-5

DO - 10.1038/s41588-022-01199-5

M3 - Journal article

C2 - 36280732

SN - 1061-4036

VL - 54

SP - 1652

EP - 1663

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Multiomics study of nonalcoholic fatty liver disease

Abstract

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