Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways

Marijana Vujkovic; David E Kaplan; Jonas Ghouse; Bao-Li Loza; Joseph Brancale; Adam Lewis; David Y Zhang; Michael G Levin; Olivia J Veatch; Josephine P Johnson; Carolin V Schneider; Anurag Verma; Kirk J Wangensteen; Eleonora Scorletti; Dipender Gill; Chigoziri Konkwo; Alexis M Garófalo; Lindsay A Guare; Tae-Wi Schwantes-An; Marco V Abreu; Helene Gellert-Kristensen; Ole B Pedersen; Christian Erikstrup; Johan S Bundgaard; Erik Sørensen; Sisse R Ostrowski; Henning Bundgaard; Kyung Min Lee; Abraham Shaked; Kim M Olthoff; Maarouf A Hoteit; Elizabeth K Speliotes; Yanhua Chen; Antonino Oliveri; Lishi Yin; Luca Vc Valenti; Francesco Malvestiti; Daniele Marchelli; Lorenzo Miano; Quentin M Anstee; Ann K Daly; Heather J Cordell; Rebecca Darlay; Niek Verweij; George Hindy; Adam Locke; Kentaro Matsuura; Sumeet K Asrani; Giuliano Testa; Luca A Lotta; Marcus B Jones; Daniel R Dochtermann; Trina M Norden-Krichmar; Craig C Teerlink; Poornima Devineni; Saiju Pyarajan; Daniel J Rader; Yasuhito Tanaka; Benjamin F Voight; Silvia Vilarinho; Lisa A Bastarache; Stefan Stender; Philip S Tsao; Timothy R Morgan; Julie A Lynch; Kyong-Mi Chang; Penn Medicine Biobank

doi:10.1101/2025.09.16.25335186

Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways

Marijana Vujkovic, David E Kaplan, Jonas Ghouse, Bao-Li Loza, Joseph Brancale, Adam Lewis, David Y Zhang, Michael G Levin, Olivia J Veatch, Josephine P Johnson, Carolin V Schneider, Anurag Verma, Kirk J Wangensteen, Eleonora Scorletti, Dipender Gill, Chigoziri Konkwo, Alexis M Garófalo, Lindsay A Guare, Tae-Wi Schwantes-An, Marco V AbreuHelene Gellert-Kristensen, Ole B Pedersen, Christian Erikstrup, Johan S Bundgaard, Erik Sørensen, Sisse R Ostrowski, Henning Bundgaard, Kyung Min Lee, Abraham Shaked, Kim M Olthoff, Maarouf A Hoteit, Elizabeth K Speliotes, Yanhua Chen, Antonino Oliveri, Lishi Yin, Luca Vc Valenti, Francesco Malvestiti, Daniele Marchelli, Lorenzo Miano, Quentin M Anstee, Ann K Daly, Heather J Cordell, Rebecca Darlay, Niek Verweij, George Hindy, Adam Locke, Kentaro Matsuura, Sumeet K Asrani, Giuliano Testa, Luca A Lotta, Marcus B Jones, Daniel R Dochtermann, Trina M Norden-Krichmar, Craig C Teerlink, Poornima Devineni, Saiju Pyarajan, Daniel J Rader, Yasuhito Tanaka, Benjamin F Voight, Silvia Vilarinho, Lisa A Bastarache, Stefan Stender, Philip S Tsao, Timothy R Morgan, Julie A Lynch, Kyong-Mi Chang, Penn Medicine Biobank

Abstract

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

Originalsprog	Engelsk
DOI	https://doi.org/10.1101/2025.09.16.25335186
Status	Udgivet - 18 sep. 2025

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10.1101/2025.09.16.25335186Licens: CC BY-NC-ND

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Vujkovic, M., Kaplan, D. E., Ghouse, J., Loza, B.-L., Brancale, J., Lewis, A., Zhang, D. Y., Levin, M. G., Veatch, O. J., Johnson, J. P., Schneider, C. V., Verma, A., Wangensteen, K. J., Scorletti, E., Gill, D., Konkwo, C., Garófalo, A. M., Guare, L. A., Schwantes-An, T.-W., ... Penn Medicine Biobank (2025). Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways. medRxiv https://doi.org/10.1101/2025.09.16.25335186

Vujkovic, M, Kaplan, DE, Ghouse, J, Loza, B-L, Brancale, J, Lewis, A, Zhang, DY, Levin, MG, Veatch, OJ, Johnson, JP, Schneider, CV, Verma, A, Wangensteen, KJ, Scorletti, E, Gill, D, Konkwo, C, Garófalo, AM, Guare, LA, Schwantes-An, T-W, Abreu, MV, Gellert-Kristensen, H, Pedersen, OB, Erikstrup, C, Bundgaard, JS , Sørensen, E , Ostrowski, SR , Bundgaard, H, Lee, KM, Shaked, A, Olthoff, KM, Hoteit, MA, Speliotes, EK, Chen, Y, Oliveri, A, Yin, L, Valenti, LV, Malvestiti, F, Marchelli, D, Miano, L, Anstee, QM, Daly, AK, Cordell, HJ, Darlay, R, Verweij, N, Hindy, G, Locke, A, Matsuura, K, Asrani, SK, Testa, G, Lotta, LA, Jones, MB, Dochtermann, DR, Norden-Krichmar, TM, Teerlink, CC, Devineni, P, Pyarajan, S, Rader, DJ, Tanaka, Y, Voight, BF, Vilarinho, S, Bastarache, LA, Stender, S, Tsao, PS, Morgan, TR, Lynch, JA, Chang, K-M & Penn Medicine Biobank 2025 'Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways' medRxiv. https://doi.org/10.1101/2025.09.16.25335186

@misc{1199bb49661442ceb53a19eb2e63b7e5,

title = "Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways",

abstract = "Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.",

author = "Marijana Vujkovic and Kaplan, \{David E\} and Jonas Ghouse and Bao-Li Loza and Joseph Brancale and Adam Lewis and Zhang, \{David Y\} and Levin, \{Michael G\} and Veatch, \{Olivia J\} and Johnson, \{Josephine P\} and Schneider, \{Carolin V\} and Anurag Verma and Wangensteen, \{Kirk J\} and Eleonora Scorletti and Dipender Gill and Chigoziri Konkwo and Gar{\'o}falo, \{Alexis M\} and Guare, \{Lindsay A\} and Tae-Wi Schwantes-An and Abreu, \{Marco V\} and Helene Gellert-Kristensen and Pedersen, \{Ole B\} and Christian Erikstrup and Bundgaard, \{Johan S\} and Erik S{\o}rensen and Ostrowski, \{Sisse R\} and Henning Bundgaard and Lee, \{Kyung Min\} and Abraham Shaked and Olthoff, \{Kim M\} and Hoteit, \{Maarouf A\} and Speliotes, \{Elizabeth K\} and Yanhua Chen and Antonino Oliveri and Lishi Yin and Valenti, \{Luca Vc\} and Francesco Malvestiti and Daniele Marchelli and Lorenzo Miano and Anstee, \{Quentin M\} and Daly, \{Ann K\} and Cordell, \{Heather J\} and Rebecca Darlay and Niek Verweij and George Hindy and Adam Locke and Kentaro Matsuura and Asrani, \{Sumeet K\} and Giuliano Testa and Lotta, \{Luca A\} and Jones, \{Marcus B\} and Dochtermann, \{Daniel R\} and Norden-Krichmar, \{Trina M\} and Teerlink, \{Craig C\} and Poornima Devineni and Saiju Pyarajan and Rader, \{Daniel J\} and Yasuhito Tanaka and Voight, \{Benjamin F\} and Silvia Vilarinho and Bastarache, \{Lisa A\} and Stefan Stender and Tsao, \{Philip S\} and Morgan, \{Timothy R\} and Lynch, \{Julie A\} and Kyong-Mi Chang and \{Penn Medicine Biobank\}",

year = "2025",

month = sep,

day = "18",

doi = "10.1101/2025.09.16.25335186",

language = "English",

series = "medRxiv",

type = "WorkingPaper",

}

TY - UNPB

T1 - Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways

AU - Vujkovic, Marijana

AU - Kaplan, David E

AU - Ghouse, Jonas

AU - Loza, Bao-Li

AU - Brancale, Joseph

AU - Lewis, Adam

AU - Zhang, David Y

AU - Levin, Michael G

AU - Veatch, Olivia J

AU - Johnson, Josephine P

AU - Schneider, Carolin V

AU - Verma, Anurag

AU - Wangensteen, Kirk J

AU - Scorletti, Eleonora

AU - Gill, Dipender

AU - Konkwo, Chigoziri

AU - Garófalo, Alexis M

AU - Guare, Lindsay A

AU - Schwantes-An, Tae-Wi

AU - Abreu, Marco V

AU - Gellert-Kristensen, Helene

AU - Pedersen, Ole B

AU - Erikstrup, Christian

AU - Bundgaard, Johan S

AU - Sørensen, Erik

AU - Ostrowski, Sisse R

AU - Bundgaard, Henning

AU - Lee, Kyung Min

AU - Shaked, Abraham

AU - Olthoff, Kim M

AU - Hoteit, Maarouf A

AU - Speliotes, Elizabeth K

AU - Chen, Yanhua

AU - Oliveri, Antonino

AU - Yin, Lishi

AU - Valenti, Luca Vc

AU - Malvestiti, Francesco

AU - Marchelli, Daniele

AU - Miano, Lorenzo

AU - Anstee, Quentin M

AU - Daly, Ann K

AU - Cordell, Heather J

AU - Darlay, Rebecca

AU - Verweij, Niek

AU - Hindy, George

AU - Locke, Adam

AU - Matsuura, Kentaro

AU - Asrani, Sumeet K

AU - Testa, Giuliano

AU - Lotta, Luca A

AU - Jones, Marcus B

AU - Dochtermann, Daniel R

AU - Norden-Krichmar, Trina M

AU - Teerlink, Craig C

AU - Devineni, Poornima

AU - Pyarajan, Saiju

AU - Rader, Daniel J

AU - Tanaka, Yasuhito

AU - Voight, Benjamin F

AU - Vilarinho, Silvia

AU - Bastarache, Lisa A

AU - Stender, Stefan

AU - Tsao, Philip S

AU - Morgan, Timothy R

AU - Lynch, Julie A

AU - Chang, Kyong-Mi

AU - Penn Medicine Biobank

PY - 2025/9/18

Y1 - 2025/9/18

N2 - Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

AB - Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

U2 - 10.1101/2025.09.16.25335186

DO - 10.1101/2025.09.16.25335186

M3 - Preprint

C2 - 41001506

T3 - medRxiv

BT - Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways

ER -

Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways

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