Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci

Nat Genet. 2017 Jun;49(6):842-847. doi: 10.1038/ng.3855. Epub 2017 Apr 24.


Complex traits arise from the interplay between genetic and environmental factors. The actions of these factors usually appear to be additive, and few compelling examples of gene-environment synergy have been documented. Here we show that adiposity significantly amplifies the effect of three sequence variants (encoding PNPLA3 p.I148M, TM6SF2 p.E167K, and GCKR p.P446L) associated with nonalcoholic fatty liver disease (NAFLD). Synergy between adiposity and genotype promoted the full spectrum of NAFLD, from steatosis to hepatic inflammation to cirrhosis. We found no evidence of strong interaction between adiposity and sequence variants influencing other adiposity-associated traits. These results indicate that adiposity augments genetic risk of NAFLD at multiple loci that confer susceptibility to hepatic steatosis through diverse metabolic mechanisms.

Publication types

  • Multicenter Study

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adiposity / genetics*
  • Alanine Transaminase / blood
  • Cohort Studies
  • Genetic Predisposition to Disease
  • Humans
  • Lipase / genetics*
  • Membrane Proteins / genetics*
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Polymorphism, Single Nucleotide
  • Triglycerides / genetics


  • Adaptor Proteins, Signal Transducing
  • GCKR protein, human
  • Membrane Proteins
  • TM6SF2 protein, human
  • Triglycerides
  • Alanine Transaminase
  • Lipase
  • adiponutrin, human