| Literature DB >> 35654975 |
Marijana Vujkovic1,2, Shweta Ramdas3, Daniel J Rader2,3, Benjamin F Voight4,5,6,7, Kyong-Mi Chang8,9, Kim M Lorenz1,3,10, Xiuqing Guo11, Rebecca Darlay12, Heather J Cordell12, Jing He13, Yevgeniy Gindin14, Chuhan Chung14, Robert P Myers14,15, Carolin V Schneider3, Joseph Park2,3, Kyung Min Lee16, Marina Serper1,2, Rotonya M Carr17, David E Kaplan1,2, Mary E Haas18, Matthew T MacLean3, Walter R Witschey19, Xiang Zhu20,21,22,23, Catherine Tcheandjieu20,24, Rachel L Kember25,26, Henry R Kranzler25,26, Anurag Verma1,3, Ayush Giri27, Derek M Klarin20,28,29, Yan V Sun30,31, Jie Huang32, Jennifer E Huffman33, Kate Townsend Creasy3, Nicholas J Hand3, Ching-Ti Liu34, Michelle T Long35, Jie Yao11, Matthew Budoff36, Jingyi Tan11, Xiaohui Li11, Henry J Lin11, Yii-Der Ida Chen11, Kent D Taylor11, Ruey-Kang Chang11, Ronald M Krauss37, Silvia Vilarinho38, Joseph Brancale38, Jonas B Nielsen39, Adam E Locke39, Marcus B Jones39, Niek Verweij39, Aris Baras39, K Rajender Reddy2, Brent A Neuschwander-Tetri40, Jeffrey B Schwimmer41, Arun J Sanyal42, Naga Chalasani43, Kathleen A Ryan44, Braxton D Mitchell44, Dipender Gill45, Andrew D Wells46,47, Elisabetta Manduchi3, Yedidya Saiman48, Nadim Mahmud49, Donald R Miller50,51, Peter D Reaven52,53, Lawrence S Phillips30,54, Sumitra Muralidhar55, Scott L DuVall16,56, Jennifer S Lee20,24, Themistocles L Assimes20,24,57, Saiju Pyarajan33,58,59, Kelly Cho33,58,59, Todd L Edwards60,61, Scott M Damrauer1,3,62, Peter W Wilson30,63, J Michael Gaziano33,58, Christopher J O'Donnell33,58,59, Amit V Khera29,59,64, Struan F A Grant3,65,66, Christopher D Brown3, Philip S Tsao20,24,57, Danish Saleheen67,68,69, Luca A Lotta39, Lisa Bastarache13, Quentin M Anstee70,71, Ann K Daly71, James B Meigs29,59,72, Jerome I Rotter11, Julie A Lynch16,56,73.
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.Entities:
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Year: 2022 PMID： 35654975 DOI： 10.1038/s41588-022-01078-z
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307