Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms

Cell. 2019 Oct 17;179(3):750-771.e22. doi: 10.1016/j.cell.2019.09.021.


Tissue-specific regulatory regions harbor substantial genetic risk for disease. Because brain development is a critical epoch for neuropsychiatric disease susceptibility, we characterized the genetic control of the transcriptome in 201 mid-gestational human brains, identifying 7,962 expression quantitative trait loci (eQTL) and 4,635 spliceQTL (sQTL), including several thousand prenatal-specific regulatory regions. We show that significant genetic liability for neuropsychiatric disease lies within prenatal eQTL and sQTL. Integration of eQTL and sQTL with genome-wide association studies (GWAS) via transcriptome-wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in schizophrenia (SCZ). Gene network analysis revealed that SCZ and autism spectrum disorder (ASD) affect distinct developmental gene co-expression modules. Yet, in each disorder, common and rare genetic variation converges within modules, which in ASD implicates superficial cortical neurons. More broadly, these data, available as a web browser and our analyses, demonstrate the genetic mechanisms by which developmental events have a widespread influence on adult anatomical and behavioral phenotypes.

Keywords: TWAS; autism; eQTL; gene networks; gene regulation; human cortical development; sQTL; schizophrenia; splicing regulation.

Publication types

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

MeSH terms

  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / metabolism
  • Autism Spectrum Disorder / pathology
  • Brain / growth & development
  • Brain / metabolism
  • Female
  • Fetus / metabolism
  • Gene Expression Regulation, Developmental
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Gestational Age
  • Humans
  • Male
  • Neurons / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics*
  • RNA Splicing / genetics
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Schizophrenia / pathology
  • Transcriptome / genetics*