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

Author:

Vujkovic MarijanaORCID,Ramdas Shweta,Lorenz Kimberly M.,Guo Xiuqing,Darlay Rebecca,Cordell Heather J.,He Jing,Gindin Yevgeniy,Chung Chuhan,Meyers Rob P,Schneider Carolin V.,Park Joseph,Lee Kyung M.,Serper Marina,Carr Rotonya M.,Kaplan David E.,Haas Mary E.ORCID,MacLean Matthew T.,Witschey Walter R.ORCID,Zhu Xiang,Tcheandjieu Catherine,Kember Rachel L.ORCID,Kranzler Henry R.,Verma Anurag,Giri Ayush,Klarin Derek M.ORCID,Sun Yan V.ORCID,Huang Jie,Huffman Jennifer,Creasy Kate Townsend,Hand Nicholas J.,Liu Ching-TiORCID,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 Katherine A.,Mitchell Braxton D.,Gill DipenderORCID,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.ORCID,Pyarajan Saiju,Cho Kelly,Edwards Todd L.,Damrauer Scott M.,Wilson Peter W.,Gaziano J. Michael,O’Donnell Christopher J.,Khera Amit V.ORCID,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.ORCID,Rader Daniel J.ORCID,Voight Benjamin F.ORCID,Chang Kyong-MiORCID,

Abstract

AbstractNonalcoholic 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-American-only and two in African-American-only analyses (P<5×10-8). 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<6.5×10-4) 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.

Publisher

Cold Spring Harbor Laboratory

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