Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci (original) (raw)

• Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Pritchard, J.K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).
  Article CAS PubMed Google Scholar
• Yang, J. et al. Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat. Genet. 47, 1114–1120 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Zuk, O., Hechter, E., Sunyaev, S.R. & Lander, E.S. The mystery of missing heritability: Genetic interactions create phantom heritability. Proc. Natl. Acad. Sci. USA 109, 1193–1198 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Purcell, S. Variance components models for gene–environment interaction in twin analysis. Twin Res. 5, 554–571 (2002).
  Article PubMed Google Scholar
• Kaprio, J. Twins and the mystery of missing heritability: the contribution of gene–environment interactions. J. Intern. Med. 272, 440–448 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Sadee, W. et al. Missing heritability of common diseases and treatments outside the protein-coding exome. Hum. Genet. 133, 1199–1215 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, L., McLeod, H.L. & Weinshilboum, R.M. Genomics and drug response. N. Engl. J. Med. 364, 1144–1153 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Samson, M. et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).
  Article CAS PubMed Google Scholar
• Barón, A.E. et al. Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes. Cancer Epidemiol. Biomarkers Prev. 23, 2829–2839 (2014).
  Article PubMed PubMed Central Google Scholar
• Reddon, H., Guéant, J.L. & Meyre, D. The importance of gene–environment interactions in human obesity. Clin. Sci. (Lond.) 130, 1571–1597 (2016).
  Article CAS Google Scholar
• Manuck, S.B. & McCaffery, J.M. Gene–environment interaction. Annu. Rev. Psychol. 65, 41–70 (2014).
  Article PubMed Google Scholar
• Ludwig, J., Viggiano, T.R., McGill, D.B. & Oh, B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434–438 (1980).
  CAS PubMed Google Scholar
• Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352–356 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Santoro, N. et al. Hepatic de novo lipogenesis in obese youth is modulated by a common variant in the GCKR gene. J. Clin. Endocrinol. Metab. 100, E1125–E1132 (2015).
  Article PubMed PubMed Central Google Scholar
• Speliotes, E.K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Browning, J.D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).
  Article PubMed Google Scholar
• Falconer, D.S. in Introduction to Quantitative Genetics 1st edn. 292–301 (Ronald Press Company, 1960).
• Thompson, W.D. Effect modification and the limits of biological inference from epidemiologic data. J. Clin. Epidemiol. 44, 221–232 (1991).
  Article CAS PubMed Google Scholar
• Voorman, A., Lumley, T., McKnight, B. & Rice, K. Behavior of QQ-plots and genomic control in studies of gene–environment interaction. PLoS One 6, e19416 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, T.A. & Sanyal, A.J. Pathophysiology guided treatment of nonalcoholic steatohepatitis. J. Gastroenterol. Hepatol. 27 (suppl. 2), 58–64 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cohen, J.C., Horton, J.D. & Hobbs, H.H. Human fatty liver disease: old questions and new insights. Science 332, 1519–1523 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Speliotes, E.K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Mancina, R.M. et al. The MBOAT7_–_TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230 (2016).
  Article CAS PubMed Google Scholar
• Smagris, E. et al. _Pnpla3_I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61, 108–118 (2015).
  Article CAS PubMed Google Scholar
• Rees, M.G. et al. Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 55, 114–122 (2012).
  Article CAS PubMed Google Scholar
• Huang, Y. et al. A feed-forward loop amplifies nutritional regulation of _PNPLA_3. Proc. Natl. Acad. Sci. USA 107, 7892–7897 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Arden, C. et al. Elevated glucose represses liver glucokinase and induces its regulatory protein to safeguard hepatic phosphate homeostasis. Diabetes 60, 3110–3120 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Smagris, E., Gilyard, S., BasuRay, S., Cohen, J.C. & Hobbs, H.H. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J. Biol. Chem. 291, 10659–10676 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Graff, M. et al. PNPLA3 gene–by–visceral adipose tissue volume interaction and the pathogenesis of fatty liver disease: the NHLBI family heart study. Int. J. Obes. (Lond.) 37, 432–438 (2013).
  Article CAS Google Scholar
• York, L.W., Puthalapattu, S. & Wu, G.Y. Nonalcoholic fatty liver disease and low-carbohydrate diets. Annu. Rev. Nutr. 29, 365–379 (2009).
  Article CAS PubMed Google Scholar
• Davis, J.N. et al. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am. J. Clin. Nutr. 92, 1522–1527 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Williams, C.D. et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124–131 (2011).
  Article PubMed Google Scholar
• Yuan, X. et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520–528 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Chambers, J.C. et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet. 43, 1131–1138 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Larrieta-Carrasco, E. et al. Association of the I148M/PNPLA3 variant with elevated alanine transaminase levels in normal-weight and overweight/obese Mexican children. Gene 520, 185–188 (2013).
  Article CAS PubMed Google Scholar
• Giudice, E.M. et al. The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS One 6, e27933 (2011).
  Article PubMed Google Scholar
• Hart, C.L., Morrison, D.S., Batty, G.D., Mitchell, R.J. & Davey Smith, G. Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. Br. Med. J. 340, c1240 (2010).
  Article Google Scholar
• Tian, C., Stokowski, R.P., Kershenobich, D., Ballinger, D.G. & Hinds, D.A. Variant in PNPLA3 is associated with alcoholic liver disease. Nat. Genet. 42, 21–23 (2010).
  Article CAS PubMed Google Scholar
• Locke, A.E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Ehret, G.B. et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011).
  Article CAS PubMed Google Scholar
• Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).
  CAS PubMed PubMed Central Google Scholar
• Neel, J.V. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am. J. Hum. Genet. 14, 353–362 (1962).
  CAS PubMed PubMed Central Google Scholar
• Browning, J.D., Cohen, J.C. & Hobbs, H.H. Patatin-like phospholipase domain–containing 3 and the pathogenesis and progression of pediatric nonalcoholic fatty liver disease. Hepatology 52, 1189–1192 (2010).
  Article CAS PubMed Google Scholar
• Szczepaniak, L.S. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 288, E462–E468 (2005).
  Article CAS PubMed Google Scholar
• Stender, S., Frikke-Schmidt, R., Nordestgaard, B.G. & Tybjaerg-Hansen, A. The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease. J. Am. Coll. Cardiol. 63, 2121–2128 (2014).
  Article CAS PubMed Google Scholar
• Victor, R.G. et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am. J. Cardiol. 93, 1473–1480 (2004).
  Article PubMed Google Scholar
• Vestberg, K. et al. Data quality of administratively collected hospital discharge data for liver cirrhosis epidemiology. J. Med. Syst. 21, 11–20 (1997).
  Article CAS PubMed Google Scholar
• Day, F.R., Loh, P.R., Scott, R.A., Ong, K.K. & Perry, J.R. A robust example of collider bias in a genetic association study. Am. J. Hum. Genet. 98, 392–393 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Burgess, S., Small, D.S. & Thompson, S.G. A review of instrumental variable estimators for Mendelian randomization. Stat. Methods Med. Res. http://dx.doi.org/10.1177/0962280215597579 (2015).