Predicting regulatory variants using a dense epigenomic mapped CNN model elucidated the molecular basis of trait-tissue associations

Nucleic Acids Res. 2021 Jan 11;49(1):53-66. doi: 10.1093/nar/gkaa1137.


Assessing the causal tissues of human complex diseases is important for the prioritization of trait-associated genetic variants. Yet, the biological underpinnings of trait-associated variants are extremely difficult to infer due to statistical noise in genome-wide association studies (GWAS), and because >90% of genetic variants from GWAS are located in non-coding regions. Here, we collected the largest human epigenomic map from ENCODE and Roadmap consortia and implemented a deep-learning-based convolutional neural network (CNN) model to predict the regulatory roles of genetic variants across a comprehensive list of epigenomic modifications. Our model, called DeepFun, was built on DNA accessibility maps, histone modification marks, and transcription factors. DeepFun can systematically assess the impact of non-coding variants in the most functional elements with tissue or cell-type specificity, even for rare variants or de novo mutations. By applying this model, we prioritized trait-associated loci for 51 publicly-available GWAS studies. We demonstrated that CNN-based analyses on dense and high-resolution epigenomic annotations can refine important GWAS associations in order to identify regulatory loci from background signals, which yield novel insights for better understanding the molecular basis of human complex disease. We anticipate our approaches will become routine in GWAS downstream analysis and non-coding variant evaluation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Causality
  • Chromatin Immunoprecipitation
  • Datasets as Topic
  • Deep Learning*
  • Epigenome*
  • Epigenomics / methods*
  • Genetic Diseases, Inborn / metabolism
  • Genome-Wide Association Study
  • Histone Code
  • Humans
  • Linkage Disequilibrium
  • Models, Genetic*
  • Molecular Sequence Annotation
  • Organ Specificity
  • Polymorphism, Single Nucleotide
  • Transcription Factors / metabolism


  • Transcription Factors