Медицинская библиотека · Nature genetics · 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.

Vujkovic Marijana, Ramdas Shweta, Lorenz Kim M, Guo Xiuqing, Darlay Rebecca, Cordell Heather J, He Jing, Gindin Yevgeniy, Chung Chuhan, Myers Robert P, Schneider Carolin V, Park Joseph, Lee Kyung Min, Serper Marina, Carr Rotonya M, Kaplan David E, Haas Mary E, MacLean Matthew T, Witschey Walter R, Zhu Xiang, Tcheandjieu Catherine, Kember Rachel L, Kranzler Henry R, Verma Anurag, Giri Ayush, Klarin Derek M, Sun Yan V, Huang Jie, Huffman Jennifer E, Creasy Kate Townsend, Hand Nicholas J, Liu Ching-Ti, Long Michelle T, Yao Jie, Budoff Matthew, Tan Jingyi, Li Xiaohui, Lin Henry J, Chen Yii-Der Ida, Taylor Kent D, Chang Ruey-Kang, Krauss Ronald M, Vilarinho Silvia, Brancale Joseph, Nielsen Jonas B, Locke Adam E, Jones Marcus B, Verweij Niek, Baras Aris, Reddy K Rajender, Neuschwander-Tetri Brent A, Schwimmer Jeffrey B, Sanyal Arun J, Chalasani Naga, Ryan Kathleen A, Mitchell Braxton D, Gill Dipender, Wells Andrew D, Manduchi Elisabetta, Saiman Yedidya, Mahmud Nadim, Miller Donald R, Reaven Peter D, Phillips Lawrence S, Muralidhar Sumitra, DuVall Scott L, Lee Jennifer S, Assimes Themistocles L, Pyarajan Saiju, Cho Kelly, Edwards Todd L, Damrauer Scott M, Wilson Peter W, Gaziano J Michael, O'Donnell Christopher J, Khera Amit V, Grant Struan F A, Brown Christopher D, Tsao Philip S, Saleheen Danish, Lotta Luca A, Bastarache Lisa, Anstee Quentin M, Daly Ann K, Meigs James B, Rotter Jerome I, Lynch Julie A, Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program, Rader Daniel J, Voight Benjamin F, Chang Kyong-Mi

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Аннотация

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.

Для цитирования: Vujkovic Marijana, Ramdas Shweta, Lorenz Kim M, Guo Xiuqing, Darlay Rebecca, Cordell Heather J, He Jing, Gindin Yevgeniy, Chung Chuhan, Myers Robert P, Schneider Carolin V, Park Joseph, Lee Kyung Min, Serper Marina, Carr Rotonya M, Kaplan David E, Haas Mary E, MacLean Matthew T, Witschey Walter R, Zhu Xiang, Tcheandjieu Catherine, Kember Rachel L, Kranzler Henry R, Verma Anurag, Giri Ayush, Klarin Derek M, Sun Yan V, Huang Jie, Huffman Jennifer E, Creasy Kate Townsend, Hand Nicholas J, Liu Ching-Ti, Long Michelle T, Yao Jie, Budoff Matthew, Tan Jingyi, Li Xiaohui, Lin Henry J, Chen Yii-Der Ida, Taylor Kent D, Chang Ruey-Kang, Krauss Ronald M, Vilarinho Silvia, Brancale Joseph, Nielsen Jonas B, Locke Adam E, Jones Marcus B, Verweij Niek, Baras Aris, Reddy K Rajender, Neuschwander-Tetri Brent A, Schwimmer Jeffrey B, Sanyal Arun J, Chalasani Naga, Ryan Kathleen A, Mitchell Braxton D, Gill Dipender, Wells Andrew D, Manduchi Elisabetta, Saiman Yedidya, Mahmud Nadim, Miller Donald R, Reaven Peter D, Phillips Lawrence S, Muralidhar Sumitra, DuVall Scott L, Lee Jennifer S, Assimes Themistocles L, Pyarajan Saiju, Cho Kelly, Edwards Todd L, Damrauer Scott M, Wilson Peter W, Gaziano J Michael, O'Donnell Christopher J, Khera Amit V, Grant Struan F A, Brown Christopher D, Tsao Philip S, Saleheen Danish, Lotta Luca A, Bastarache Lisa, Anstee Quentin M, Daly Ann K, Meigs James B, Rotter Jerome I, Lynch Julie A, Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program, Rader Daniel J, Voight Benjamin F, Chang Kyong-Mi. 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. 2022. DOI: 10.1038/s41588-022-01078-z.

Предметные рубрики MeSH

Alanine Transaminase Alpha-Ketoglutarate-Dependent Dioxygenase FTO Genome-Wide Association Study Humans Intracellular Signaling Peptides and Proteins Lipase Membrane Proteins Non-alcoholic Fatty Liver Disease Polymorphism, Single Nucleotide Protein Serine-Threonine Kinases

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