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

Nat Genet. 2022 Jun;54(6):761-771. doi: 10.1038/s41588-022-01078-z. Epub 2022 Jun 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alanine Transaminase
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Genome-Wide Association Study*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Lipase / genetics
  • Membrane Proteins / genetics
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Protein Serine-Threonine Kinases / antagonists & inhibitors


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • TRIB1 protein, human
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • Alanine Transaminase
  • Protein Serine-Threonine Kinases
  • Lipase

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