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

Stefan Stender, Julia Kozlitina, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Helen H. Hobbs, Jonathan C. Cohen

Research output: Contribution to journalArticlepeer-review

249 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)842-847
Number of pages6
JournalNature genetics
Issue number6
StatePublished - Jun 1 2017

ASJC Scopus subject areas

  • Genetics


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