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

被引：12

作者：

Ghouse, Jonas ^{[1
,2
]}

Sveinbjornsson, Gardar ^{[3
]}

Vujkovic, Marijana ^{[4
,5
,6
]}

Seidelin, Anne-Sofie ^{[7
]}

Gellert-Kristensen, Helene ^{[7
]}

Ahlberg, Gustav ^{[2
]}

Tragante, Vinicius ^{[3
]}

Rand, Soren A. ^{[1
,2
]}

Brancale, Joseph ^{[8
,9
]}

Vilarinho, Silvia ^{[8
]}

Lundegaard, Pia Rengtved ^{[2
]}

Sorensen, Erik ^{[10
]}

Erikstrup, Christian ^{[11
]}

Bruun, Mie Topholm ^{[12
]}

Jensen, Bitten Aagaard ^{[13
]}

Brunak, Soren ^{[14
]}

Banasik, Karina ^{[15
]}

Ullum, Henrik ^{[16
]}

Verweij, Niek ^{[17
]}

Lotta, Luca ^{[17
]}

Baras, Aris ^{[16
]}

Mirshahi, Tooraj ^{[18
]}

Carey, David J. ^{[4
,5
]}

Kaplan, David E. ^{[4
,5
]}

Lynch, Julie ^{[19
,20
]}

Morgan, Timothy ^{[21
,22
]}

Schwantes-An, Tae-Hwi ^{[23
]}

Dochtermann, Daniel R. ^{[24
]}

Pyarajan, Saiju ^{[25
,26
]}

Tsao, Philip S. ^{[27
,28
]}

Laisk, Triin ^{[29
]}

Magi, Reedik ^{[30
,31
]}

Kozlitina, Julia ^{[30
]}

Tybjaerg-Hansen, Anne ^{[7
]}

Jones, David ^{[31
]}

Knowlton, Kirk U. ^{[32
,33
]}

Nadauld, Lincoln ^{[34
]}

Ferkingstad, Egil ^{[3
]}

Bjornsson, Einar S. ^{[35
,36
]}

Ulfarsson, Magnus O. ^{[3
,37
]}

Sturluson, Arni ^{[3
]}

Sulem, Patrick ^{[3
]}

Pedersen, Ole B. ^{[38
,39
]}

Ostrowski, Sisse R. ^{[38
]}

Gudbjartsson, Daniel F. ^{[3
,40
]}

Stefansson, Kari ^{[3
]}

Olesen, Morten Salling ^{[1
]}

Chang, Kyong-Mi

Holm, Hilma

Bundgaard, Henning ^{[38
]}

机构：

[1] Rigshosp, Copenhagen Univ Hosp, Dept Cardiol, Copenhagen, Denmark

[2] Univ Copenhagen, Dept Biomed Sci, Cardiac Genet Grp, Copenhagen, Denmark

[3] deCODE Genet Amgen, Reykjavik, Iceland

[4] Corporal Michael J Crescenz VA Med Ctr, Philadelphia, PA USA

[5] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA USA

[6] Univ Penn, Perelman Sch Med, Dept Biostat Epidemiol & Informat, Philadelphia, PA USA

[7] Rigshosp, Copenhagen Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark

[8] Yale Sch Med, Dept Internal Med, Sect Digest Dis, New Haven, CT USA

[9] Yale Sch Med, Dept Pathol, New Haven, CT USA

[10] Rigshosp, Copenhagen Univ Hosp, Dept Clin Immunol, Copenhagen, Denmark

[11] Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark

[12] Odense Univ Hosp, Dept Clin Immunol, Odense, Denmark

[13] Aalborg Univ Hosp, Dept Clin Immunol, Aalborg, Denmark

[14] Univ Copenhagen, Novo Nord Fdn Ctr Prot Res, Fac Hlth & Med Sci, Translat Dis Syst Biol, Copenhagen, Denmark

[15] Copenhagen Univ Hosp Hvidovre, Dept Obstet & Gynaecol, Copenhagen, Denmark

[16] Statens Serum Inst, Copenhagen, Denmark

[17] Regeneron Pharmaceut Inc, Regeneron Genet Ctr, Tarrytown, NY USA

[18] Geisinger Hlth Syst, Dept Mol & Funct Genom, Danville, PA USA

[19] VA Informat & Comp Infrastruct VINCI, Salt Lake City, UT USA

[20] Univ Utah, Sch Med, Dept Internal Med, Div Epidemiol, Salt Lake City, UT USA

[21] Vet Affairs Long Beach Healthcare Syst, Gerontol Sect, Long Beach, CA USA

[22] Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA

[23] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN USA

[24] VA Boston HealthCare Syst, Ctr Data & Computat Sci, Boston, MA USA

[25] Brigham & Womens Hosp, Dept Med, Boston, MA USA

[26] Harvard Med Sch, Boston, MA USA

[27] VA Palo Alto, Palo Alto Epidemiol Res & Informat Ctr Genom, Palo Alto, CA USA

[28] Stanford Univ, Sch Med, Dept Med, Stanford, CA USA

[29] Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia

[30] Univ Texas Southwestern Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX USA

[31] Precis Genom, Intermt Healthcare, St George, UT USA

[32] Intermt Heart Inst, Intermt Med Ctr, Salt Lake City, UT USA

[33] Univ Utah, Sch Med, Salt Lake City, UT USA

[34] Stanford Univ, Sch Med, Stanford, CA USA

[35] Univ Iceland, Fac Med, Reykjavik, Iceland

[36] Landspitali Natl Univ Hosp Iceland, Internal Med & Emergency Serv, Reykjavik, Iceland

[37] Univ Iceland, Fac Elect & Comp Engn, Reykjavik, Iceland

[38] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark

[39] Zealand Univ Hosp, Dept Clin Immunol, Koge, Denmark

[40] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

来源：

NATURE GENETICS | 2024年 / 56卷 / 05期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; RISK; DISEASE;

D O I：

10.1038/s41588-024-01720-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and gamma-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. A multi-ancestry genome-wide association study of liver cirrhosis and its associated endophenotypes identifies and validates 14 risk variants. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

引用

页码：827 / 837

页数：18

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