Mapping cis-regulatory elements in human neurons links psychiatric disease heritability and activity-regulated transcriptional programs

Cell Rep. 2022 May 31;39(9):110877. doi: 10.1016/j.celrep.2022.110877.

Abstract

Genome-wide association studies (GWASs) have identified hundreds of loci associated with psychiatric diseases, yet there is a lack of understanding of disease pathophysiology. Common risk variants can shed light on the underlying molecular mechanisms; however, identifying causal variants remains challenging. We map cis-regulatory elements in human neurons derived from pluripotent stem cells. This system allows us to determine enhancers that activate the transcription of neuronal activity-regulated gene programs, which are thought to be critical for synaptic plasticity and are not possible to identify from postmortem tissues. Using the activity-by-contact model, we create variant-to-gene maps to interpret the function of GWAS variants. Our work nominates a subset of variants to elucidate the molecular mechanisms involving GWAS-significant loci. It also highlights that in vitro human cellular models are a powerful platform for identifying and mechanistic studies of human trait-associated genetic variants in cell states that are inaccessible from other types of human samples.

Keywords: CP: Molecular biology; CP: Neuroscience; cis-regulatory elements; human stem cells; neurons; non-coding variation; psychiatric diseases.

Publication types

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

MeSH terms

  • Genome-Wide Association Study*
  • Humans
  • Mental Disorders* / genetics
  • Mental Disorders* / metabolism
  • Neurons / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics