A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease

Jiantao Ma, Jana Nano, Jingzhong Ding, Yinan Zheng, Rachel Hennein, Chunyu Liu, Elizabeth K. Speliotes, Tianxiao Huan, Ci Song, Michael M. Mendelson, Roby Joehanes, Michelle T. Long, Liming Liang, Jennifer A. Smith, Lindsay M. Reynolds, Mohsen Ghanbari, Taulant Muka, Joyce B.J. Van Meurs, Louise J.M. Alferink, Oscar H. FrancoAbbas Dehghan, Scott Ratliff, Wei Zhao, Lawrence Bielak, Sharon L.R. Kardia, Patricia A. Peyser, Hongyan Ning, Lisa B. VanWagner, Donald M. Lloyd-Jones, John Jeffrey Carr, Philip Greenland, Alice H. Lichtenstein, Frank B. Hu, Yongmei Liu, Lifang Hou, Sarwa Darwish Murad, Daniel Levy

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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 DNAmethylation signatures of NAFLD across racial/ethnic groups.

Original languageEnglish (US)
Pages (from-to)1073-1083
Number of pages11
Issue number5
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


Dive into the research topics of 'A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease'. Together they form a unique fingerprint.

Cite this