A genome-wide association study for nonalcoholic fatty liver disease identifies novel genetic loci and trait-relevant candidate genes in the Million Veteran Program.
By
Marijana Vujkovic,
Shweta Ramdas,
Kimberly M. Lorenz,
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 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,
Jerome I. Rotter,
Xiuqing Guo,
Jie Yao,
Matthew Budoff,
Katherine A. Ryan,
Braxton D Mitchell,
Dipender Gill,
Andrew D. Wells,
Elisabetta Manduchi,
Yedidya Saiman,
Nadim Mahmud,
Donald R. Miller,
Peter D. Reaven,
Laurence 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,
John M. Gaziano,
Christopher J. O’Donnell,
Amit V Khera,
Struan F.A. Grant,
Christopher D. Brown,
Philip S. Tsao,
Danish Saleheen,
James B Meigs,
Julie A. 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 prevalent, heritable trait that can progress to cancer and liver failure. Using our recently developed proxy definition for NAFLD based on chronic liver enzyme elevation without other causes of liver disease or alcohol misuse, we performed a multi-ancestry genome-wide association study in the Million Veteran Program with 90,408 NAFLD cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance of which 70 were novel, with an additional European-American specific and two African-American specific loci. Twelve of these loci were also significantly associated with quantitative hepatic fat on radiological imaging (n=44,289). Gene prioritization based on coding annotations, gene expression from GTEx, and functional genomic annotation identified candidate genes at 97% of loci. At eight loci, the allele associated with lower gene expression in liver was also associated with reduced risk of NAFLD, suggesting potential therapeutic relevance. Functional genomic annotation and gene-set enrichment demonstrated that associated loci were relevant to liver biology. We expand the catalog of genes influencing NAFLD, and provide a novel resource to understand its disease initiation, progression and therapy.
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