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

By Marijana Vujkovic, Shweta Ramdas, Kimberly M. Lorenz, Xiuqing Guo, Rebecca Darlay, Heather J. Cordell, Jing He, Yevgeniy Gindin, Chuhan Chung, Rob P Meyers, Carolin V. Schneider, Joseph Park, Kyung M. Lee, Marina Serper, Rotonya M Carr, David E. Kaplan, Mary E. Haas, Matthew T MacLean, Walter R. Witschey, Xiang Zhu, Catherine Tcheandjieu, Rachel L Kember, Henry R. Kranzler, Anurag Verma, Ayush Giri, Derek M. Klarin, Yan V. Sun, Jie Huang, Jennifer Huffman, Kate Townsend Creasy, Nicholas J Hand, Ching-Ti Liu, Michelle T. Long, Jie Yao, Matthew Budoff, Jingyi Tan, Xiaohui Li, Henry J Lin, Yii-Der Ida Chen, Kent D. Taylor, Ruey-Kang Chang, Ronald M Krauss, Silvia Vilarinho, Joseph Brancale, Jonas B Nielsen, Adam E Locke, Marcus B. Jones, Niek Verweij, Aris Baras, K. Rajender Reddy, Brent A. Neuschwander-Tetri, Jeffrey B. Schwimmer, Arun J. Sanyal, Naga Chalasani, Katherine A. Ryan, Braxton D Mitchell, Dipender Gill, Andrew D. Wells, Elisabetta Manduchi, Yedidya Saiman, Nadim Mahmud, Donald R. Miller, Peter D. Reaven, Lawrence S. Phillips, Sumitra Muralidhar, Scott L. DuVall, Jennifer S. Lee, Themistocles L Assimes, Saiju Pyarajan, Kelly Cho, Todd L Edwards, Scott M. Damrauer, Peter W. Wilson, J. Michael Gaziano, Christopher J. O?Donnell, Amit V. Khera, Struan F.A. Grant, Christopher D. Brown, Philip S. Tsao, Danish Saleheen, Luca A Lotta, Lisa Bastarache, Quentin M. Anstee, Ann K. Daly, James B Meigs, Jerome I. Rotter, Julie Lynch, Daniel J Rader, Benjamin F. Voight, Kyong-Mi Chang

Posted 02 Jan 2021
medRxiv DOI: 10.1101/2020.12.26.20248491

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic alanine aminotransferase elevation (cALT) without other liver diseases, we performed a trans-ancestry genome-wide association study in the Million Veteran Program including 90,408 cALT cases and 128,187 controls. In the Discovery stage, seventy-seven loci exceeded genome-wide significance (including 25 without prior NAFLD or ALT associations) with one additional locus identified in European-only and two in African-American-only analyses (P<5x10-8). External replication in cohorts with NAFLD defined by histology (7,397 cases, 56,785 controls) or liver fat extracted from radiologic imaging (n=44,289) validated 17 SNPs (P<6.5x10-4) of which 9 were novel (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH, and IFI30). Pleiotropy analysis showed that 61 of 77 trans-ancestry and all 17 validated 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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