Comprehensive functional genomic resource and integrative model for the human brain

Science. 2018 Dec 14;362(6420):eaat8464. doi: 10.1126/science.aat8464.

Abstract

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / metabolism*
  • Datasets as Topic
  • Deep Learning
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic
  • Epigenomics
  • Gene Expression Regulation*
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Humans
  • Mental Disorders / genetics*
  • Quantitative Trait Loci
  • Single-Cell Analysis
  • Transcriptome

Grant support