A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

被引：129

作者：

Vujkovic, Marijana ^{[1
,2
]}

Ramdas, Shweta ^{[3
]}

Lorenz, Kim M. ^{[1
,3
,4
]}

Guo, Xiuqing ^{[5
]}

Darlay, Rebecca ^{[6
]}

Cordell, Heather J. ^{[6
]}

He, Jing ^{[7
]}

Gindin, Yevgeniy ^{[8
]}

Chung, Chuhan ^{[8
]}

Myers, Robert P. ^{[8
,9
]}

Schneider, Carolin V. ^{[3
]}

Park, Joseph ^{[2
,3
]}

Lee, Kyung Min ^{[10
]}

Serper, Marina ^{[1
,2
]}

Carr, Rotonya M. ^{[11
]}

Kaplan, David E. ^{[1
,2
]}

Haas, Mary E. ^{[12
]}

MacLean, Matthew T. ^{[3
]}

Witschey, Walter R. ^{[13
]}

Zhu, Xiang ^{[14
,15
,16
,17
]}

Tcheandjieu, Catherine ^{[14
,18
]}

Kember, Rachel L. ^{[19
,20
]}

Kranzler, Henry R. ^{[19
,20
]}

Verma, Anurag ^{[1
,3
]}

Giri, Ayush ^{[21
]}

Klarin, Derek M. ^{[14
,22
,23
]}

Sun, Yan V. ^{[24
,25
]}

Huang, Jie ^{[26
]}

Huffman, Jennifer E. ^{[27
]}

Townsend Creasy, Kate ^{[3
]}

Hand, Nicholas J. ^{[3
]}

Liu, Ching-Ti ^{[28
]}

Long, Michelle T. ^{[29
]}

Yao, Jie ^{[5
]}

Budoff, Matthew ^{[30
]}

Tan, Jingyi ^{[5
]}

Li, Xiaohui ^{[5
]}

Lin, Henry J. ^{[5
]}

Chen, Yii-Der Ida ^{[5
]}

Taylor, Kent D. ^{[5
]}

Chang, Ruey-Kang ^{[5
]}

Krauss, Ronald M. ^{[31
]}

Vilarinho, Silvia ^{[32
,33
]}

Brancale, Joseph ^{[32
,33
]}

Nielsen, Jonas B. ^{[34
]}

Locke, Adam E. ^{[34
]}

Jones, Marcus B. ^{[34
]}

Verweij, Niek ^{[34
]}

Baras, Aris ^{[34
]}

Reddy, K. Rajender ^{[2
]}

机构：

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

[2] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Syst Pharmacol & Translat Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA

[5] Harbor UCLA Med Ctr, Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA 90509 USA

[6] Newcastle Univ, Populat Hlth Sci Inst, Newcastle Upon Tyne, Tyne & Wear, England

[7] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA

[8] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA

[9] Liver Co, Palo Alto, CA USA

[10] VA Salt Lake City Hlth Care Syst, Salt Lake City, UT USA

[11] Univ Washington, Div Gastroenterol, Seattle, WA 98195 USA

[12] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[13] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA

[14] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA

[15] Penn State Univ, Dept Stat, University Pk, PA 16802 USA

[16] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA

[17] Stanford Univ, Dept Stat, Stanford, CA 94305 USA

[18] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[19] Corporal Michael J Crescenz VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA

[20] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA

[21] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37232 USA

[22] Stanford Univ, Sch Med, Div Vasc Surg, Palo Alto, CA 94304 USA

[23] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[24] Atlanta VA Med Ctr, Decatur, GA USA

[25] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA

[26] Southern Univ Sci & Technol, Sch Publ Hlth & Emergency Management, Shenzhen, Guangdong, Peoples R China

[27] VA Boston Healthcare Syst, Boston, MA USA

[28] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[29] Boston Univ, Sch Med, Dept Med, Gastroenterol Sect, Boston, MA 02118 USA

[30] Harbor UCLA Med Ctr, Dept Cardiol, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[31] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA

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

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

[34] Regeneron Genet Ctr, Tarrytown, NY USA

[35] St Louis Univ, Dept Internal Med, St Louis, MO 63103 USA

[36] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA

[37] Virginia Commonwealth Univ, Dept Internal Med, Sch Med, Richmond, VA USA

[38] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA

[39] Univ Maryland, Dept Med, Program Personalized & Genom Med, Div Endocrinol Diabet & Nutr,Sch Med, Baltimore, MD 21201 USA

[40] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[41] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA

[42] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA

[43] Temple Univ, Temple Univ Hosp, Lewis Katz Sch Med, Sect Hepatol,Dept Med, Philadelphia, PA 19122 USA

[44] Univ Penn, Dept Med, Div Gastroenterol, Perelman Sch Med, Philadelphia, PA 19104 USA

[45] Bedford VA Healthcare Syst, Ctr Healthcare Org & Implementat Res, Bedford, MA USA

[46] Univ Massachusetts, Dept Biomed & Nutr Sci, Ctr Populat Hlth, Lowell, MA USA

[47] Phoenix VA Hlth Care Syst, Phoenix, AZ USA

[48] Univ Arizona, Coll Med, Phoenix, AZ USA

[49] Emory Univ, Sch Med, Div Endocrinol, Atlanta, GA USA

[50] Vet Hlth Adm, Off Res & Dev, Washington, DC USA

来源：

NATURE GENETICS | 2022年 / 54卷 / 06期

基金：

美国国家卫生研究院;

关键词：

HEPATOCYTE-LIKE CELLS; GENE-EXPRESSION; CONFERS SUSCEPTIBILITY; IDENTIFIES LOCI; PROTEIN; ATLAS; VARIANTS; FEATURES; STEATOHEPATITIS; HERITABILITY;

D O I：

10.1038/s41588-022-01078-z

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 x 10(-8)). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 x 10(-4)), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD. A multiancestry genome-wide association study of chronic alanine aminotransferase elevation identifies candidate risk loci for nonalcoholic fatty liver disease, with replication in external cohorts defined by histology or imaging.

引用

页码：761 / +

页数：22

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