Deep learning predicts DNA methylation regulatory variants in specific brain cell types and enhances fine mapping for brain disorders

Sci Adv. 2025 Jan 3;11(1):eadn1870. doi: 10.1126/sciadv.adn1870. Epub 2025 Jan 1.

Abstract

DNA methylation (DNAm) is essential for brain development and function and potentially mediates the effects of genetic risk variants underlying brain disorders. We present INTERACT, a transformer-based deep learning model to predict regulatory variants affecting DNAm levels in specific brain cell types, leveraging existing single-nucleus DNAm data from the human brain. We show that INTERACT accurately predicts cell type-specific DNAm profiles, achieving an average area under the receiver operating characteristic curve of 0.99 across cell types. Furthermore, INTERACT predicts cell type-specific DNAm regulatory variants, which reflect cellular context and enrich the heritability of brain-related traits in relevant cell types. We demonstrate that incorporating predicted variant effects and DNAm levels of CpG sites enhances the fine mapping for three brain disorders-schizophrenia, depression, and Alzheimer's disease-and facilitates mapping causal genes to particular cell types. Our study highlights the power of deep learning in identifying cell type-specific regulatory variants, which will enhance our understanding of the genetics of complex traits.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Brain Diseases / genetics
  • Brain Diseases / pathology
  • Brain* / metabolism
  • CpG Islands
  • DNA Methylation*
  • Deep Learning*
  • Genetic Predisposition to Disease
  • Humans
  • Schizophrenia / genetics
  • Schizophrenia / metabolism
  • Schizophrenia / pathology