Brain-trait-associated variants impact cell-type-specific gene regulation during neurogenesis

Am J Hum Genet. 2021 Sep 2;108(9):1647-1668. doi: 10.1016/j.ajhg.2021.07.011. Epub 2021 Aug 19.

Abstract

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.

Keywords: cell-type specificity; common genetic variants; expression/splicing quantitative loci; genome-wide association study; neurogenesis; neuropsychiatric disorders; transcriptome-wide association study.

Publication types

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

MeSH terms

  • Alleles
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Cell Differentiation
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Mapping
  • Educational Status
  • Female
  • Fetus
  • Gene Expression Regulation, Developmental*
  • Genetic Predisposition to Disease
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Male
  • Neocortex / cytology
  • Neocortex / growth & development
  • Neocortex / metabolism*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurogenesis / genetics*
  • Neurons / cytology
  • Neurons / metabolism*
  • Neuroticism
  • Parkinson Disease / diagnosis
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Primary Cell Culture
  • Prognosis
  • Quantitative Trait Loci*
  • Schizophrenia / diagnosis
  • Schizophrenia / genetics
  • Schizophrenia / metabolism
  • Transcriptome

Substances

  • CENPW protein, human
  • Chromatin
  • Chromosomal Proteins, Non-Histone