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

Jennifer K Forsyth; Daniel Nachun; Michael J Gandal; Daniel H Geschwind; Ariana E Anderson; Giovanni Coppola; Carrie E Bearden

doi:10.1016/j.biopsych.2019.06.029

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.

Authors

Jennifer K Forsyth¹, Daniel Nachun², Michael J Gandal³, Daniel H Geschwind⁴, Ariana E Anderson², Giovanni Coppola⁵, Carrie E Bearden⁶

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California. Electronic address: jforsyth@mednet.ucla.edu.
² Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California.
³ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California; Brain Research Institute, University of California, Los Angeles, Los Angeles, California.
⁴ Department of Human Genetics, University of California, Los Angeles, Los Angeles, California; Department of Neurology, University of California, Los Angeles, Los Angeles, California; Brain Research Institute, University of California, Los Angeles, Los Angeles, California.
⁵ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California; Department of Neurology, University of California, Los Angeles, Los Angeles, California; Brain Research Institute, University of California, Los Angeles, Los Angeles, California.
⁶ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California; Department of Psychology, University of California, Los Angeles, Los Angeles, California; Brain Research Institute, University of California, Los Angeles, Los Angeles, California. Electronic address: cbearden@mednet.ucla.edu.

Abstract

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

Substances

MicroRNAs
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding