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

Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium; VA Million Veteran Program

doi:10.1038/s41588-022-01078-z

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

Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

Abstract

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 × 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 × 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.

Original language	English
Pages (from-to)	761-771
Number of pages	11
Journal	Nature Genetics
Volume	54
Issue number	6
DOIs	https://doi.org/10.1038/s41588-022-01078-z
State	Published - Jun 2022
Externally published	Yes

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10.1038/s41588-022-01078-z

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Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, & VA Million Veteran Program (2022). A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. Nature Genetics, 54(6), 761-771. https://doi.org/10.1038/s41588-022-01078-z

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

abstract = "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 × 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 × 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.",

author = "{Regeneron Genetics Center} and {Geisinger-Regeneron DiscovEHR Collaboration} and {EPoS Consortium} and {VA Million Veteran Program} and Marijana Vujkovic and Shweta Ramdas and Lorenz, {Kim M.} and Xiuqing Guo and Rebecca Darlay and Cordell, {Heather J.} and Jing He and Yevgeniy Gindin and Chuhan Chung and Myers, {Robert P.} and Schneider, {Carolin V.} and Joseph Park and Lee, {Kyung Min} and Marina Serper and Carr, {Rotonya M.} and Kaplan, {David E.} and Haas, {Mary E.} and MacLean, {Matthew T.} and Witschey, {Walter R.} and Xiang Zhu and Catherine Tcheandjieu and Kember, {Rachel L.} and Kranzler, {Henry R.} and Anurag Verma and Ayush Giri and Klarin, {Derek M.} and Sun, {Yan V.} and Jie Huang and Huffman, {Jennifer E.} and {Townsend Creasy}, Kate and Hand, {Nicholas J.} and Liu, {Ching Ti} and Long, {Michelle T.} and Jie Yao and Matthew Budoff and Jingyi Tan and Xiaohui Li and Lin, {Henry J.} and Chen, {Yii Der Ida} and Taylor, {Kent D.} and Chang, {Ruey Kang} and Krauss, {Ronald M.} and Silvia Vilarinho and Joseph Brancale and Nielsen, {Jonas B.} and Locke, {Adam E.} and Jones, {Marcus B.} and Niek Verweij and Aris Baras and Saiju Pyarajan",

note = "Publisher Copyright: {\textcopyright} 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2022",

month = jun,

doi = "10.1038/s41588-022-01078-z",

language = "English",

volume = "54",

pages = "761--771",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium & VA Million Veteran Program 2022, 'A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation', Nature Genetics, vol. 54, no. 6, pp. 761-771. https://doi.org/10.1038/s41588-022-01078-z

A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. / Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium et al.
In: Nature Genetics, Vol. 54, No. 6, 06.2022, p. 761-771.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

AU - Regeneron Genetics Center

AU - Geisinger-Regeneron DiscovEHR Collaboration

AU - EPoS Consortium

AU - VA Million Veteran Program

AU - Vujkovic, Marijana

AU - Ramdas, Shweta

AU - Lorenz, Kim M.

AU - Guo, Xiuqing

AU - Darlay, Rebecca

AU - Cordell, Heather J.

AU - He, Jing

AU - Gindin, Yevgeniy

AU - Chung, Chuhan

AU - Myers, Robert P.

AU - Schneider, Carolin V.

AU - Park, Joseph

AU - Lee, Kyung Min

AU - Serper, Marina

AU - Carr, Rotonya M.

AU - Kaplan, David E.

AU - Haas, Mary E.

AU - MacLean, Matthew T.

AU - Witschey, Walter R.

AU - Zhu, Xiang

AU - Tcheandjieu, Catherine

AU - Kember, Rachel L.

AU - Kranzler, Henry R.

AU - Verma, Anurag

AU - Giri, Ayush

AU - Klarin, Derek M.

AU - Sun, Yan V.

AU - Huang, Jie

AU - Huffman, Jennifer E.

AU - Townsend Creasy, Kate

AU - Hand, Nicholas J.

AU - Liu, Ching Ti

AU - Long, Michelle T.

AU - Yao, Jie

AU - Budoff, Matthew

AU - Tan, Jingyi

AU - Li, Xiaohui

AU - Lin, Henry J.

AU - Chen, Yii Der Ida

AU - Taylor, Kent D.

AU - Chang, Ruey Kang

AU - Krauss, Ronald M.

AU - Vilarinho, Silvia

AU - Brancale, Joseph

AU - Nielsen, Jonas B.

AU - Locke, Adam E.

AU - Jones, Marcus B.

AU - Verweij, Niek

AU - Baras, Aris

AU - Pyarajan, Saiju

PY - 2022/6

Y1 - 2022/6

N2 - 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 × 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 × 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.

AB - 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 × 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 × 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.

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U2 - 10.1038/s41588-022-01078-z

DO - 10.1038/s41588-022-01078-z

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AN - SCOPUS:85132074767

SN - 1061-4036

VL - 54

SP - 761

EP - 771

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

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