Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia
Open accessAbstract
Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT–BPD and SCZ–BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes,IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions—the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions.
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Multiple neuronal and synaptic signaling pathways have been previously demonstrated to be downregulated in a diminishing gradient across ASD, SCZ, and BD brains without clear disease-specific signals.
“Multiple neuronal and synaptic signaling pathways have been previously demonstrated to be downregulated in a diminishing gradient across ASD, SCZ, and BD brains without identification of clear disease-specific signals for these neuronal-synaptic gene sets (1, 2, 16, 19, 56, 57).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [56]
Direct genetic evidence links ASD and schizophrenia.
“alongside direct genetic evidence that links ASD and schizophrenia (Cantor and Geschwind, 2008;Ellis et al, 2016;Zhou et al, 2016).”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Ellis et al, 2016
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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder
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- Authors
- Ellis, S. E., Panitch, R., West, A. B., & Arking, D. E.
- Affiliations
- Johns Hopkins University (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Arking, D E
- Venue
- Translational Psychiatry
- Published
- 2016-05-24
- Volume
- 6
- Issue
- 5
- Pages
- e817-e817
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5070061
- OpenAlex
- W2952547283
- Cited by
- 48
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 6
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Simons Foundation (137603)
- Simons Foundation Autism Research Initiative
- National Institute of Mental Health (R01MH100027, R01MH081754)
- National Institute of General Medical Sciences (T32GM007814)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, schizophrenia, bipolar disorder, cortical transcriptome, gene expression overlap, down-regulated genes, neurotransmission, synaptic regulation, postmortem brain, genetic association signals, shared etiology
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Autistic Disorder, Bipolar Disorder, Cerebral Cortex, Child, Child, Preschool, Female, Frontal Lobe, Humans, Male, Middle Aged, RNA, Messenger, Schizophrenia, Down-Regulation, Linear Models, Case-Control Studies, Prefrontal Cortex, Sequence Analysis, RNA, Microglia, Guanine Nucleotide Exchange Factors, Gene Expression Profiling, Young Adult, High-Throughput Nucleotide Sequencing
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