1 Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, and Framingham Heart Study, Framingham, MA.
2 Nutrition Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA.
3 Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
4 Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology, Neuherberg, Germany.
5 German Center for Diabetes Research, München-Neuherberg, Germany.
6 Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC.
7 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
8 Department of Biostatistics, Boston University, Boston, MA.
9 University of Michigan Medical School, Ann Arbor, MI.
10 Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
11 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
12 Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, MA.
13 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
14 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
15 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
16 Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
17 Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
18 Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
19 Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, U.K.
20 Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
21 Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN.
22 Cardiovascular Nutrition Laboratory, USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
23 Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
24 Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, and Framingham Heart Study, Framingham, MA firstname.lastname@example.org.
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.