Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 Copy Number Variant-Mediated Risk for Neuropsychiatric Disorders

Biol Psychiatry. 2020 Jan 15;87(2):150-163. doi: 10.1016/j.biopsych.2019.06.029. Epub 2019 Jul 11.


Background: 22q11.2 copy number variants are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear.

Methods: Using a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and gene expression signatures from SCZ and ASD postmortem cortex to 1) organize genes into the developmental cellular and molecular systems within which they operate, 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum, and 3) elucidate pathways and individual genes through which 22q11.2 copy number variants may confer risk for each disorder.

Results: Polygenic risk for SCZ and ASD converged on partially overlapping neurodevelopmental modules involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for modules involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network during development that disproportionately affected SCZ-associated and ASD-associated neurodevelopmental modules, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation.

Conclusions: This approach offers a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant, multigene copy number variants contribute to disease risk.

Keywords: 22q11.2 copy number variants; Autism spectrum disorder; Brain development; Functional genomics; Genetic risk; Schizophrenia.

Publication types

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

MeSH terms

  • Autism Spectrum Disorder* / genetics
  • Autistic Disorder* / genetics
  • DNA Copy Number Variations
  • Genome-Wide Association Study
  • Humans
  • MicroRNAs*
  • RNA-Binding Proteins
  • Schizophrenia* / genetics


  • MicroRNAs
  • RNA-Binding Proteins