Abstract
Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy.
Key points
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Nonalcoholic fatty liver disease (NAFLD) is a liver disorder with high heritability, and no approved pharmacotherapy to date.
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Although our understanding of the genetic underpinnings of NAFLD has advanced, known risk variants explain only a small fraction of heritability, suggesting the existence of ‘missing heritability’.
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There is evidence for shared genetic modifiers and common pathophysiological pathways that link NAFLD, other liver diseases and related metabolic disorders.
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Research has now progressed beyond genome-wide association studies (GWAS) to broader, causal and functional discovery via multi-trait GWAS, phenome-wide association studies (PheWAS), Mendelian randomization and functional annotation studies.
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The next wave of genetic studies should have substantial translational implications for both drug discovery and personalization of medicine.
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References
Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018).
Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).
Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J. Hepatol. 69, 896–904 (2018).
Guthold, R., Stevens, G. A., Riley, L. M. & Bull, F. C. Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants. Lancet Glob. Health 6, e1077–e1086 (2018).
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).
Wong, R. J. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 148, 547–555 (2015).
Adams, L. A. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129, 113–121 (2005).
Trefts, E., Gannon, M. & Wasserman, D. H. The liver. Curr. Biol. 27, R1147–R1151 (2017).
Gastaldelli, A. Fatty liver disease: the hepatic manifestation of metabolic syndrome. Hypertens. Res. 33, 546–547 (2010).
Kotronen, A. & Yki-Jarvinen, H. Fatty liver — a novel component of the metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 28, 27–38 (2008).
Lonardo, A., Nascimbeni, F., Mantovani, A. & Targher, G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J. Hepatol. 68, 335–352 (2018).
Targher, G., Day, C. P. & Bonora, E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 363, 1341–1350 (2010).
Eslam, M. & George, J. Genetic and epigenetic mechanisms of NASH. Hepatol. Int. 10, 394–406 (2016).
Cui, J. et al. Shared genetic effects between hepatic steatosis and fibrosis: a prospective twin study. Hepatology 64, 1547–1558 (2016).
Schwimmer, J. B. et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136, 1585–1592 (2009).
Eslam, M., Valenti, L. & Romeo, S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68, 268–279 (2018).
Caussy, C. et al. Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. J. Clin. Invest. 127, 2697–2704 (2017).
Loomba, R. et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 149, 1784–1793 (2015).
Wagenknecht, L. E. et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity 17, 1240–1246 (2009).
Palmer, N. D. et al. Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent. Hepatology 58, 966–975 (2013).
Stunkard, A. J., Foch, T. T. & Hrubec, Z. A twin study of human obesity. JAMA 256, 51–54 (1986).
Poulsen, P., Kyvik, K. O., Vaag, A. & Beck-Nielsen, H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance — a population-based twin study. Diabetologia 42, 139–145 (1999).
Hottenga, J. J. et al. Heritability and stability of resting blood pressure. Twin Res. Hum. Genet. 8, 499–508 (2005).
Knoblauch, H. et al. Heritability analysis of lipids and three gene loci in twins link the macrophage scavenger receptor to HDL cholesterol concentrations. Arterioscler. Thromb. Vasc. Biol. 17, 2054–2060 (1997).
Zdravkovic, S. et al. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J. Intern. Med. 252, 247–254 (2002).
Haines, J. L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).
Eslam, M. & George, J. Genome-wide association studies and hepatitis C: harvesting the benefits of the genomic revolution. Semin. Liver Dis. 35, 402–420 (2015).
Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
Sookoian, S. et al. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J. Lipid Res. 50, 2111–2116 (2009).
Valenti, L. et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209–1217 (2010).
Liu, Y. L. et al. Carriage of the PNPLA3 rs738409 C>G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 61, 75–81 (2014).
Jenkins, C. M. et al. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J. Biol. Chem. 279, 48968–48975 (2004).
Bruschi, F. V. et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 65, 1875–1890 (2017).
Pirazzi, C. et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum. Mol. Genet. 23, 4077–4085 (2014).
Eslam, M. et al. Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology 64, 34–46 (2016).
Holmen, O. L. et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat. Genet. 46, 345–351 (2014).
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).
Liu, Y. L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).
Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506–514 (2015).
Mahdessian, H. et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc. Natl Acad. Sci. USA 111, 8913–8918 (2014).
Li, T.-T. et al. TM6SF2: a novel target for plasma lipid regulation. Atherosclerosis 268, 170–176 (2018).
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).
Valenti, L., Alisi, A. & Nobili, V. Unraveling the genetics of fatty liver in obese children: additive effect of P446L GCKR and I148M PNPLA3 polymorphisms. Hepatology 55, 661–663 (2012).
Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).
Ma, Y. et al. 17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease. Hepatology 69, 1504–1519 (2019).
Metwally, M. et al. A polymorphism in the irisin-encoding gene (FNDC5) associates with hepatic steatosis by differential miRNA binding to the 3′UTR. J. Hepatol. 70, 494–500 (2019).
Buch, S. et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat. Genet. 47, 1443–1448 (2015).
Vigano, M. et al. Patatin-like phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis B. Hepatology 58, 1245–1252 (2013).
Milano, M. et al. Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients. Hepatology 62, 111–117 (2015).
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.e6 (2016).
Donati, B. et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci. Rep. 7, 4492 (2017).
Thabet, K. et al. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat. Commun. 7, 12757 (2016).
Thabet, K. et al. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology 65, 1840–1850 (2017).
Patin, E. et al. Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology 143, 1244–1252.e12 (2012).
Musso, G. et al. MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat. Hum. Mol. Genet. 26, 1747–1758 (2017).
Petta, S. et al. MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 64, 682–690 (2016).
Ochodnicky, P. et al. Increased circulating and urinary levels of soluble TAM receptors in diabetic nephropathy. Am. J. Pathol. 187, 1971–1983 (2017).
Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat. Genet. 41, 1100–1104 (2009).
Tanaka, Y. et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat. Genet. 41, 1105–1109 (2009).
Thomas, D. L. et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461, 798–801 (2009).
Eslam, M. et al. Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat. Commun. 6, 6422 (2015).
Eslam, M. et al. FibroGENE: a gene-based model for staging liver fibrosis. J. Hepatol. 64, 390–398 (2016).
Petta, S. et al. Interferon lambda 4 rs368234815 TT>delta G variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 66, 1885–1893 (2017).
Eslam, M. et al. IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis. Nat. Genet. 49, 795–800 (2017).
Eichler, E. E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11, 446–450 (2010).
Sookoian, S. & Pirola, C. J. Genetic predisposition in nonalcoholic fatty liver disease. Clin. Mol. Hepatol. 23, 1–12 (2017).
Trerotola, M., Relli, V., Simeone, P. & Alberti, S. Epigenetic inheritance and the missing heritability. Hum. Genomics 9, 17 (2015).
Timpson, N. J., Greenwood, C. M. T., Soranzo, N., Lawson, D. J. & Richards, J. B. Genetic architecture: the shape of the genetic contribution to human traits and disease. Nat. Rev. Genet. 19, 110–124 (2018).
Stender, S. et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat. Genet. 49, 842–847 (2017).
Solovieff, N., Cotsapas, C., Lee, P. H., Purcell, S. M. & Smoller, J. W. Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet. 14, 483–495 (2013).
Chen, Y. S. & Lubberstedt, T. Molecular basis of trait correlations. Trends Plant Sci. 15, 454–461 (2010).
Pickrell, J. K. et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709–717 (2016).
Visscher, P. M. & Yang, J. A plethora of pleiotropy across complex traits. Nat. Genet. 48, 707–708 (2016).
Chesmore, K., Bartlett, J. & Williams, S. M. The ubiquity of pleiotropy in human disease. Hum. Genet. 137, 39–44 (2018).
Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).
Cotsapas, C. & Hafler, D. A. Immune-mediated disease genetics: the shared basis of pathogenesis. Trends Immunol. 34, 22–26 (2013).
O’Donovan, M. C. & Owen, M. J. The implications of the shared genetics of psychiatric disorders. Nat. Med. 22, 1214–1219 (2016).
Hobbs, B. D. et al. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat. Genet. 49, 426–432 (2017).
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
Verma, A. & Ritchie, M. D. Current scope and challenges in phenome-wide association studies. Curr. Epidemiol. Rep. 4, 321–329 (2017).
Sookoian, S. et al. Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level. Am. J. Clin. Nutr. 103, 422–434 (2016).
Radcke, S., Dillon, J. F. & Murray, A. L. A systematic review of the prevalence of mildly abnormal liver function tests and associated health outcomes. Eur. J. Gastroenterol. Hepatol. 27, 1–7 (2015).
Oh, R. C., Hustead, T. R., Ali, S. M. & Pantsari, M. W. Mildly elevated liver transaminase levels: causes and evaluation. Am. Fam. Physician 96, 709–715 (2017).
Mahady, S. E. et al. Elevated liver enzymes and mortality in older individuals a prospective cohort study. J. Clin. Gastroenterol. 51, 439–445 (2017).
Loomba, R. et al. Genetic covariance between λ-glutamyl transpeptidase and fatty liver risk factors: role of β2-adrenergic receptor genetic variation in twins. Gastroenterology 139, 836–845.e1 (2010).
Caussy, C. et al. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology 68, 918–932 (2018).
Byrne, C. D. & Targher, G. NAFLD: a multisystem disease. J. Hepatol. 62, S47–S64 (2015).
Mahajan, A. et al. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat. Genet. 50, 559–571 (2018).
Simons, N. et al. PNPLA3, TM6SF2, and MBOAT7 genotypes and coronary artery disease. Gastroenterology 152, 912–913 (2017).
Ruschenbaum, S. et al. Patatin-like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events. Hepatol. Commun. 2, 798–806 (2018).
Liu, D. J. et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 49, 1758–1766 (2017).
Meffert, P. J. et al. The PNPLA3 SNP rs738409:G allele is associated with increased liver disease-associated mortality but reduced overall mortality in a population-based cohort. J. Hepatol. 68, 858–860 (2018).
Diogo, D. et al. Phenome-wide association studies across large population cohorts support drug target validation. Nat. Commun. 9, 4285 (2018).
Chen, Z. M. et al. China Kadoorie Biobank of 0.5 million people: survey methods, baseline characteristics and long-term follow-up. Int. J. Epidemiol. 40, 1652–1666 (2011).
White, H. D. et al. Darapladib for preventing ischemic events in stable coronary heart disease. N. Engl. J. Med. 370, 1702–1711 (2014).
Fall, T. et al. The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis. PLOS Med. 10, e1001474 (2013).
Shea, J. L., Randell, E. W. & Sun, G. A. The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-ray absorptiometry. Obesity 19, 624–630 (2011).
Munoz-Garach, A., Cornejo-Pareja, I. & Tinahones, F. J. Does metabolically healthy obesity exist? Nutrients 8, 320 (2016).
Despres, J. P. Body fat distribution and risk of cardiovascular disease an update. Circulation 126, 1301–1313 (2012).
Loos, R. J. F. & Kilpelainen, T. O. Genes that make you fat, but keep you healthy. J. Intern. Med. 284, 450–463 (2018).
Shungin, D. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518, 187–196 (2015).
Fehlert, E. et al. Genetic determination of body fat distribution and the attributive influence on metabolism. Obesity 25, 1277–1283 (2017).
Lotta, L. A. et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat. Genet. 49, 17–26 (2017).
Ji, Y. et al. Genome-wide and abdominal MRI-imaging data provides evidence that a genetically determined favourable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease and hypertension. Diabetes 68, 207–219 (2019).
Yaghootkar, H. et al. Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension, and heart disease. Diabetes 65, 2448–2460 (2016).
Willecke, F. et al. Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice. Arterioscler. Thromb. Vasc. Biol. 35, 102–110 (2015).
Gusarova, V. et al. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes. Nat. Commun. 9, 2252 (2018).
Conen, D. et al. Use of a mendelian randomization approach to assess the causal relation of γ-glutamyltransferase with blood pressure and serum insulin levels. Am. J. Epidemiol. 172, 1431–1441 (2010).
Chen, S. C. C. et al. Liver fat, hepatic enzymes, alkaline phosphatase and the risk of incident type 2 diabetes: a prospective study of 132,377 adults. Sci. Rep. 7, 4649 (2017).
Noordam, R., Smit, R. A. J., Postmus, I., Trompet, S. & van Heemst, D. Assessment of causality between serum gamma-glutamyltransferase and type 2 diabetes mellitus using publicly available data: a Mendelian randomization study. Int. J. Epidemiol. 45, 1953–1960 (2016).
Dongiovanni, P. et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J. Intern. Med. 283, 356–370 (2018).
Loomba, R. et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 56, 943–951 (2012).
Wild, S. H. et al. Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission. Diabetes Care 41, 341–347 (2018).
Preiss, D. et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 305, 2556–2564 (2011).
Fall, T. et al. Using genetic variants to assess the relationship between circulating lipids and type 2 diabetes. Diabetes 64, 2676–2684 (2015).
Swerdlow, D. I. et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 385, 351–361 (2015).
Zhu, Z. H. et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat. Commun. 9, 224 (2018).
Li, N. S. et al. Pleiotropic effects of lipid genes on plasma glucose, HbA(1c), and HOMA-IR levels. Diabetes 63, 3149–3158 (2014).
De Silva, N. M. G. et al. Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance. Diabetes 60, 1008–1018 (2011).
Xu, L. et al. Mendelian randomization estimates of alanine aminotransferase with cardiovascular disease: Guangzhou Biobank Cohort study. Hum. Mol. Genet. 26, 430–437 (2017).
Liu, J. X., Yeung, S. L. A., Lin, S. L., Leung, G. M. & Schooling, C. M. Liver enzymes and risk of ischemic heart disease and type 2 diabetes mellitus: a Mendelian randomization study. Sci. Rep. 6, 38813 (2016).
Lauridsen, B. K. et al. Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals. Eur. Heart J. 39, 385–393 (2018).
Zheng, J. et al. Recent developments in Mendelian randomization studies. Curr. Epidemiol. Rep. 4, 330–345 (2017).
Soderberg, C. et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 51, 595–602 (2010).
Vilar-Gomez, E. et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology 155, 443–457.e17 (2018).
Kanai, M. et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat. Genet. 50, 390–400 (2018).
Hall, M. A. et al. Detection of pleiotropy through a phenome-wide association study (PheWAS) of epidemiologic data as part of the environmental architecture for genes linked to environment (EAGLE) study. PLOS Genet. 10, e1004678 (2014).
Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).
Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).
Claussnitzer, M. et al. FTO obesity variant circuitry and adipocyte browning in humans. N. Engl. J. Med. 373, 895–907 (2015).
Smemo, S. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371–375 (2014).
Cronin, R. M. et al. Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index. Front. Genet. 5, 250 (2014).
Rao, A. S. et al. Large-scale phenome-wide association study of PCSK9 variants demonstrates protection against ischemic stroke. Circ. Genom. Precis. Med. 11, e002162 (2018).
Ruscica, M. et al. Liver fat accumulation is associated with circulating PCSK9. Ann. Med. 48, 384–391 (2016).
Lee, S. et al. Network analyses identify liver-specific targets for treating liver diseases. Mol. Syst. Biol. 13, 938 (2017).
Theocharidou, E. et al. The role of PCSK9 in the pathogenesis of non-alcoholic fatty liver disease and the effect of PCSK9 inhibitors. Curr. Pharm. Des. 24, 3654–3657 (2018).
Leung, C., Rivera, L., Furness, J. B. & Angus, P. W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 13, 412–425 (2016).
Sanyal, A. et al. BMS-986036 (pegylated FGF21) in patients with non-alcoholic steatohepatitis: a phase 2 study. J. Hepatol. 66, S89–S90 (2017).
Frayling, T. M. et al. A common allele in FGF21 associated with sugar intake is associated with body shape, lower total body-fat percentage, and higher blood pressure. Cell Rep. 23, 327–336 (2018).
Gallego-Durán, R. et al. Genetic and functional analysis of FGF21 in NAFLD/NASH [abstract THU 472]. J. Hepatol. 68 (Suppl. 1), S342–S343 (2018).
Jiang, S. et al. The single nucleotide polymorphism rs499765 is associated with fibroblast growth factor 21 and nonalcoholic fatty liver disease in a Chinese population with normal glucose tolerance. J. Nutrigenet. Nutrigenomics 7, 121–129 (2014).
Cheung, C. Y. Y. et al. An exome-chip association analysis in Chinese subjects reveals a functional missense variant of GCKR that regulates FGF21 levels. Diabetes 66, 1723–1728 (2017).
Qayyum, F. et al. Genetic variants in CYP7A1 and risk of myocardial infarction and symptomatic gallstone disease. Eur. Heart J. 39, 2106–2116 (2018).
Hoyles, L. et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 24, 1070–1080 (2018).
Wang, J. et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat. Genet. 48, 1396–1406 (2016).
Bonder, M. J. et al. The effect of host genetics on the gut microbiome. Nat. Genet. 48, 1407–1412 (2016).
Hall, A. B., Tolonen, A. C. & Xavier, R. J. Human genetic variation and the gut microbiome in disease. Nat. Rev. Genet. 18, 690–699 (2017).
Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 8, 845 (2017).
Dashti HS, M. J., Lane J. M. & Saxena R. Multitrait genome-wide association analysis of macronutrient intake identifies 12 novel loci for dietary intake and unravels genetic overlap with lifestyle traits and cardiometabolic diseases. Diabetes 67 (Suppl. 1), 176-OR (2018).
Pettinelli, P. et al. Altered hepatic genes related to retinol metabolism and plasma retinol in patients with non-alcoholic fatty liver disease. PLOS ONE 13, e0205747 (2018).
Baselli, G. & Valenti, L. Beyond fat accumulation, NAFLD genetics converges on lipid droplet biology. J. Lipid Res. 60, 7–8 (2019).
Tyler, A. L., Asselbergs, F. W., Williams, S. M. & Moore, J. H. Shadows of complexity: what biological networks reveal about epistasis and pleiotropy. Bioessays 31, 220–227 (2009).
Li, L. et al. Identification of type 2 diabetes subgroups through topological analysis of patient similarity. Sci. Transl. Med. 7, 311ra174 (2015).
Udler, M. S. et al. Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: a soft clustering analysis. PLOS Med. 15, e1002654 (2018).
Winkler, T. W. et al. A joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications. Nat. Commun. 9, 1946 (2018).
Chakrabarti, A. M. et al. Target-specific precision of CRISPR-mediated genome editing. Mol. Cell 73, 699–713.e6 (2019).
Scott, A. How CRISPR is transforming drug discovery. Nature 555, S10–S11 (2018).
Ratziu, V., Bellentani, S., Cortez-Pinto, H., Day, C. & Marchesini, G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J. Hepatol. 53, 372–384 (2010).
Imajo, K. et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 150, 626–637.e7 (2016).
Yoneda, M. et al. Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD). Gut. 56, 1330–1331 (2007).
Daniels, S. J. et al. ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology 69, 1075–1086 (2019).
Angulo, P. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45, 846–854 (2007).
Stunkard, A. J., Harris, J. R., Pedersen, N. L. & Mcclearn, G. E. The body-mass index of twins who have been reared apart. N. Engl. J. Med. 322, 1483–1487 (1990).
Jermendy, G. et al. Effect of genetic and environmental influences on cardiometabolic risk factors: a twin study. Cardiovasc. Diabetol. 10, 96 (2011).
Goode, E. L., Cherny, S. S., Christian, J. C., Jarvik, G. P. & de Andrade, M. Heritability of longitudinal measures of body mass index and lipid and lipoprotein levels in aging twins. Twin Res. Hum. Genet. 10, 703–711 (2007).
Pietilainen, K. H. et al. Distribution and heritability of BMI in Finnish adolescents aged 16y and 17y: a study of 4884 twins and 2509 singletons. Int. J. Obes. Relat. Metab. Disord. 23, 107–115 (1999).
Kaprio, J. et al. Concordance for type-1 (insulin-dependent) and type-2 (non-insulin-dependent) diabetes-mellitus in a population-based cohort of twins in Finland. Diabetologia 35, 1060–1067 (1992).
Newman, B. et al. Concordance for type-2 (non-insulin-dependent) diabetes-mellitus in male twins. Diabetologia 30, 763–768 (1987).
Medici, F., Hawa, M., Ianari, A., Pyke, D. A. & Leslie, R. D. G. Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia 42, 146–150 (1999).
Almgren, P. et al. Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study. Diabetologia 54, 2811–2819 (2011).
Hottenga, J. J., Whitfield, J. B., de Geus, E. J. C., Boomsma, D. I. & Martin, N. G. Heritability and stability of resting blood pressure in Australian twins. Twin Res. Hum. Genet. 9, 205–209 (2006).
van Rijn, M. J. E. et al. Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes. J. Hypertens. 25, 565–570 (2007).
Wienke, A., Holm, N. V., Skytthe, A. & Yashin, A. I. The heritability of mortality due to heart diseases: a correlated frailty model applied to Danish twins. Twin Res. 4, 266–274 (2001).
Acknowledgements
M.E. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, National Health and Medical Research Council of Australia (NHMRC) Program Grants (APP1053206 and APP1149976) and Project Grants (APP1107178 and APP1108422).
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Glossary
- Metabolic syndrome
-
A cluster of risk factors that are associated with insulin resistance and future cardiovascular disease risk. According to the Adult Treatment Panel-III, metabolic syndrome is defined as the presence of abnormalities in at least three of the five components: elevated fasting glucose, high blood pressure, hypertriglyceridaemia, low HDL cholesterol level and elevated waist circumference.
- Heritability
-
A statistical analysis that estimates the proportion of trait variation that is attributable to genetic variation among individuals. Heritability varies according to the studied population.
- Genome-wide association study
-
(GWAS). An examination of a large number (hundreds of thousands) of common single-nucleotide polymorphisms across the genome of many cases and controls of a particular trait to determine whether any variant is associated with the trait.
- Lipoproteins
-
Lipoproteins are complex particles with a core containing cholesterol esters and triglycerides surrounded by a lipid membrane; they contain proteins called apolipoproteins, which enable lipoprotein formation and function.
- Lipogenesis
-
The metabolic process of synthesizing fatty acids from acetyl-CoA subunits for storage as fat.
- Lands cycle
-
A metabolic remodelling pathway in the endoplasmic reticulum. The cycle is one of the major routes for acyl remodelling to modify the fatty acid composition of phospholipids.
- Phenome-wide association studies
-
(PheWAS). An unbiased systematic approach to test for associations between a specific genetic variant or series of variants, and a wide range of phenotypes in large cohorts.
- Gene effects
-
The estimation of the genetic determination for a particular trait using mathematical models that allows one to distinguish between environmental and genetic contributions.
- HOMA-IR
-
Homeostatic Model Assessment of Insulin Resistance, a surrogate measure of insulin resistance.
- Mendelian randomization studies
-
An analysis that incorporates genetic variants that are predicted to be independent of confounding factors into epidemiological studies as instrumental tools to infer causality of a risk factor or of a biomarker in a particular disease.
- Phenomics
-
The systematic study of phenomes, a set of various phenotypes.
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Eslam, M., George, J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat Rev Gastroenterol Hepatol 17, 40–52 (2020). https://doi.org/10.1038/s41575-019-0212-0
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DOI: https://doi.org/10.1038/s41575-019-0212-0
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