Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

Jonas Ghouse; Gardar Sveinbjörnsson; Marijana Vujkovic; Anne-Sofie Seidelin; Helene Gellert-Kristensen; Gustav Ahlberg; Vinicius Tragante; Søren A Rand; Joseph Brancale; Silvia Vilarinho; Pia Rengtved Lundegaard; Erik Sørensen; Christian Erikstrup; Mie Topholm Bruun; Bitten Aagaard Jensen; Søren Brunak; Karina Banasik; Henrik Ullum; Niek Verweij; Luca Lotta; Aris Baras; Tooraj Mirshahi; David J Carey; David E Kaplan; Julie Lynch; Timothy Morgan; Tae-Hwi Schwantes-An; Daniel R Dochtermann; Saiju Pyarajan; Philip S Tsao; Triin Laisk; Reedik Mägi; Julia Kozlitina; Anne Tybjærg-Hansen; David Jones; Kirk U Knowlton; Lincoln Nadauld; Egil Ferkingstad; Einar S Björnsson; Magnus O Ulfarsson; Árni Sturluson; Patrick Sulem; Ole B Pedersen; Sisse R Ostrowski; Daniel F Gudbjartsson; Kari Stefansson; Morten Salling Olesen; Kyong-Mi Chang; Henning Bundgaard; Stefan Stender; DBDS Genomic Consortium

doi:10.1038/s41588-024-01720-y

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

Jonas Ghouse, Gardar Sveinbjörnsson, Marijana Vujkovic, Anne-Sofie Seidelin, Helene Gellert-Kristensen, Gustav Ahlberg, Vinicius Tragante, Søren A Rand, Joseph Brancale, Silvia Vilarinho, Pia Rengtved Lundegaard, Erik Sørensen, Christian Erikstrup, Mie Topholm Bruun, Bitten Aagaard Jensen, Søren Brunak, Karina Banasik, Henrik Ullum, Niek Verweij, Luca LottaAris Baras, Tooraj Mirshahi, David J Carey, David E Kaplan, Julie Lynch, Timothy Morgan, Tae-Hwi Schwantes-An, Daniel R Dochtermann, Saiju Pyarajan, Philip S Tsao, Triin Laisk, Reedik Mägi, Julia Kozlitina, Anne Tybjærg-Hansen, David Jones, Kirk U Knowlton, Lincoln Nadauld, Egil Ferkingstad, Einar S Björnsson, Magnus O Ulfarsson, Árni Sturluson, Patrick Sulem, Ole B Pedersen, Sisse R Ostrowski, Daniel F Gudbjartsson, Kari Stefansson, Morten Salling Olesen, Kyong-Mi Chang, Henning Bundgaard, Stefan Stender, DBDS Genomic Consortium

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Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	56
Sider (fra-til)	827–837
Antal sider	18
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-024-01720-y
Status	Udgivet - 2024

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10.1038/s41588-024-01720-yLicens: CC BY

FullltextForlagets udgivne version, 2,31 MBLicens: CC BY

Citationsformater

Ghouse, J., Sveinbjörnsson, G., Vujkovic, M., Seidelin, A-S., Gellert-Kristensen, H., Ahlberg, G., Tragante, V., Rand, S. A., Brancale, J., Vilarinho, S., Lundegaard, P. R., Sørensen, E., Erikstrup, C., Bruun, M. T., Jensen, B. A., Brunak, S., Banasik, K., Ullum, H., Verweij, N., ... DBDS Genomic Consortium (2024). Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis. Nature Genetics, 56, 827–837. https://doi.org/10.1038/s41588-024-01720-y

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis. / Ghouse, Jonas; Sveinbjörnsson, Gardar; Vujkovic, Marijana; Seidelin, Anne-Sofie; Gellert-Kristensen, Helene; Ahlberg, Gustav; Tragante, Vinicius; Rand, Søren A; Brancale, Joseph; Vilarinho, Silvia; Lundegaard, Pia Rengtved; Sørensen, Erik; Erikstrup, Christian; Bruun, Mie Topholm; Jensen, Bitten Aagaard; Brunak, Søren ; Banasik, Karina; Ullum, Henrik; Verweij, Niek; Lotta, Luca; Baras, Aris; Mirshahi, Tooraj; Carey, David J; Kaplan, David E; Lynch, Julie; Morgan, Timothy; Schwantes-An, Tae-Hwi; Dochtermann, Daniel R; Pyarajan, Saiju; Tsao, Philip S; Laisk, Triin; Mägi, Reedik; Kozlitina, Julia; Tybjærg-Hansen, Anne; Jones, David; Knowlton, Kirk U; Nadauld, Lincoln; Ferkingstad, Egil; Björnsson, Einar S; Ulfarsson, Magnus O; Sturluson, Árni; Sulem, Patrick; Pedersen, Ole B ; Ostrowski, Sisse R; Gudbjartsson, Daniel F; Stefansson, Kari; Olesen, Morten Salling; Chang, Kyong-Mi; Bundgaard, Henning ; Stender, Stefan; DBDS Genomic Consortium.

I: Nature Genetics, Bind 56, 2024, s. 827–837.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Ghouse, J, Sveinbjörnsson, G, Vujkovic, M, Seidelin, A-S, Gellert-Kristensen, H, Ahlberg, G, Tragante, V, Rand, SA, Brancale, J, Vilarinho, S, Lundegaard, PR, Sørensen, E, Erikstrup, C, Bruun, MT, Jensen, BA, Brunak, S , Banasik, K, Ullum, H, Verweij, N, Lotta, L, Baras, A, Mirshahi, T, Carey, DJ, Kaplan, DE, Lynch, J, Morgan, T, Schwantes-An, T-H, Dochtermann, DR, Pyarajan, S, Tsao, PS, Laisk, T, Mägi, R, Kozlitina, J, Tybjærg-Hansen, A, Jones, D, Knowlton, KU, Nadauld, L, Ferkingstad, E, Björnsson, ES, Ulfarsson, MO, Sturluson, Á, Sulem, P, Pedersen, OB , Ostrowski, SR, Gudbjartsson, DF, Stefansson, K, Olesen, MS, Chang, K-M, Bundgaard, H , Stender, S & DBDS Genomic Consortium 2024, 'Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis', Nature Genetics, bind 56, s. 827–837. https://doi.org/10.1038/s41588-024-01720-y

Ghouse, Jonas ; Sveinbjörnsson, Gardar ; Vujkovic, Marijana ; Seidelin, Anne-Sofie ; Gellert-Kristensen, Helene ; Ahlberg, Gustav ; Tragante, Vinicius ; Rand, Søren A ; Brancale, Joseph ; Vilarinho, Silvia ; Lundegaard, Pia Rengtved ; Sørensen, Erik ; Erikstrup, Christian ; Bruun, Mie Topholm ; Jensen, Bitten Aagaard ; Brunak, Søren ; Banasik, Karina ; Ullum, Henrik ; Verweij, Niek ; Lotta, Luca ; Baras, Aris ; Mirshahi, Tooraj ; Carey, David J ; Kaplan, David E ; Lynch, Julie ; Morgan, Timothy ; Schwantes-An, Tae-Hwi ; Dochtermann, Daniel R ; Pyarajan, Saiju ; Tsao, Philip S ; Laisk, Triin ; Mägi, Reedik ; Kozlitina, Julia ; Tybjærg-Hansen, Anne ; Jones, David ; Knowlton, Kirk U ; Nadauld, Lincoln ; Ferkingstad, Egil ; Björnsson, Einar S ; Ulfarsson, Magnus O ; Sturluson, Árni ; Sulem, Patrick ; Pedersen, Ole B ; Ostrowski, Sisse R ; Gudbjartsson, Daniel F ; Stefansson, Kari ; Olesen, Morten Salling ; Chang, Kyong-Mi ; Bundgaard, Henning ; Stender, Stefan ; DBDS Genomic Consortium. / Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis. I: Nature Genetics. 2024 ; Bind 56. s. 827–837.

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abstract = "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.",

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T1 - Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

AU - Ghouse, Jonas

AU - Sveinbjörnsson, Gardar

AU - Vujkovic, Marijana

AU - Seidelin, Anne-Sofie

AU - Gellert-Kristensen, Helene

AU - Ahlberg, Gustav

AU - Tragante, Vinicius

AU - Rand, Søren A

AU - Brancale, Joseph

AU - Vilarinho, Silvia

AU - Lundegaard, Pia Rengtved

AU - Sørensen, Erik

AU - Erikstrup, Christian

AU - Bruun, Mie Topholm

AU - Jensen, Bitten Aagaard

AU - Brunak, Søren

AU - Banasik, Karina

AU - Ullum, Henrik

AU - Verweij, Niek

AU - Lotta, Luca

AU - Baras, Aris

AU - Mirshahi, Tooraj

AU - Carey, David J

AU - Kaplan, David E

AU - Lynch, Julie

AU - Morgan, Timothy

AU - Schwantes-An, Tae-Hwi

AU - Dochtermann, Daniel R

AU - Pyarajan, Saiju

AU - Tsao, Philip S

AU - Laisk, Triin

AU - Mägi, Reedik

AU - Kozlitina, Julia

AU - Tybjærg-Hansen, Anne

AU - Jones, David

AU - Knowlton, Kirk U

AU - Nadauld, Lincoln

AU - Ferkingstad, Egil

AU - Björnsson, Einar S

AU - Ulfarsson, Magnus O

AU - Sturluson, Árni

AU - Sulem, Patrick

AU - Pedersen, Ole B

AU - Ostrowski, Sisse R

AU - Gudbjartsson, Daniel F

AU - Stefansson, Kari

AU - Olesen, Morten Salling

AU - Chang, Kyong-Mi

AU - Bundgaard, Henning

AU - Stender, Stefan

AU - DBDS Genomic Consortium

PY - 2024

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N2 - 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.

AB - 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.

U2 - 10.1038/s41588-024-01720-y

DO - 10.1038/s41588-024-01720-y

M3 - Journal article

C2 - 38632349

VL - 56

SP - 827

EP - 837

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -