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 M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, He J, Gindin Y, Chung C, Myers RP, Schneider CV, Park J, Lee KM, Serper M, Carr RM, Kaplan DE, Haas ME, MacLean MT, Witschey WR, Zhu X, Tcheandjieu C, Kember RL, Kranzler HR, Verma A, Giri A, Klarin DM, Sun YV, Huang J, Huffman JE, Creasy KT, Hand NJ, Liu CT, Long MT, Yao J, Budoff M, Tan J, Li X, Lin HJ, Chen YI, Taylor KD, Chang RK, Krauss RM, Vilarinho S, Brancale J, Nielsen JB, Locke AE, Jones MB, Verweij N, Baras A, Reddy KR, Neuschwander-Tetri BA, Schwimmer JB, Sanyal AJ, Chalasani N, Ryan KA, Mitchell BD, Gill D, Wells AD, Manduchi E, Saiman Y, Mahmud N, Miller DR, Reaven PD, Phillips LS, Muralidhar S, DuVall SL, Lee JS, Assimes TL, Pyarajan S, Cho K, Edwards TL, Damrauer SM, Wilson PW, Gaziano JM, O'Donnell CJ, Khera AV, Grant SFA, Brown CD, Tsao PS, Saleheen D, Lotta LA, Bastarache L, Anstee QM, Daly AK, Meigs JB, Rotter JI, Lynch JA, Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program, Rader DJ, Voight BF, Chang KM. 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 Jun 1; 54(6):761-771.

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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). 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), 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.