Adiposity Amplifies the Genetic Risk of Fatty Liver Disease Conferred by Multiple Loci

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 year

  2017

• Venue

  Nature Genetics

• Publication date

  2017-04-24

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ng.3855PMID 28436986PMCID 5562020
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The importance of gene-environment interactions in human obesity.

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• Inactivation of Tm6sf2, a Gene Defective in Fatty Liver Disease, Impairs Lipidation but Not Secretion of Very Low Density Lipoproteins*

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• The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease.

  2014cited by this paper
• Gene-environment interaction.

  2014cited by this paper
• Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis

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• Connectivity-based neurofeedback: Dynamic causal modeling for real-time fMRI☆

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  2012cited by this paper
• Twins and the mystery of missing heritability: the contribution of gene–environment interactions

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• Pathophysiology guided treatment of nonalcoholic steatohepatitis

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  2012cited by this paper
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  2011cited by this paper
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  2010cited by this paper
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  2010cited by this paper
• Nonalcoholic fatty liver disease and low-carbohydrate diets.

  2009cited by this paper
• Finding the missing heritability of complex diseases

  2009cited by this paper
• The Vote of Acute Medical Inpatients

  2009cited by this paper
• Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.

  2008cited by this paper
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  2008cited by this paper
• Appendix S1

  2006cited by this paper
• Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity

  2005cited by this paper
• Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.

  2005cited by this paper
• Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity

  2004cited by this paper
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  2004cited by this paper
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  2004cited by this paper
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  2002cited by this paper
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  2001cited by this paper
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  1997cited by this paper
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  1996cited by this paper
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  1996cited by this paper
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  1991cited by this paper
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  1985cited by this paper
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  1980cited by this paper
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  1962cited by this paper

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