Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis
Open accessPublished version of a preprint
Abstract
Genome-wide association studies have identified 108 schizophrenia risk loci, but biological mechanisms for individual loci are largely unknown. Using developmental, genetic and illness-based RNA sequencing expression analysis in human brain, we characterized the human brain transcriptome around these loci and found enrichment for developmentally regulated genes with novel examples of shifting isoform usage across pre- and postnatal life. We found widespread expression quantitative trait loci (eQTLs), including many with transcript specificity and previously unannotated sequence that were independently replicated. We leveraged this general eQTL database to show that 48.1% of risk variants for schizophrenia associate with nearby expression. We lastly found 237 genes significantly differentially expressed between patients and controls, which replicated in an independent dataset, implicated synaptic processes, and were strongly regulated in early development. These findings together offer genetics- and diagnosis-related targets for better modeling of schizophrenia risk. This resource is publicly available at http://eqtl.brainseq.org/phase1 .
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Many high-risk SZ genes are functionally implicated in synaptic transmission.
“and/or are functionally implicated in synaptic transmission 162,163.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [163]
DGE effect sizes were concordant with previous RNA-seq studies of individual disorders.
“and with previous RNA-Seq studies of individual disorders (ASD: ⍴=0.96, ref (19); SCZ ⍴=0.78, ref (2); SCZ ⍴=0.80, ref (24); BD ⍴=0.85, ref (1); Spearman ⍴ of log2FC, all P’s<10−16).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [24]
Previous studies identified alterations in local splicing events in ASD and in smaller cohorts in SCZ and BD.
“Previous studies have identified alterations in local splicing events in ASD (19, 30) and in smaller cohorts in SCZ (2, 24) and BD (31).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [24]
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References 55 · Cited by 364
Research works printed but not linked: 4
- [5]Nellore A Human splicing diversity across the Sequence Read Archive. bioRxiv, doi: 10.1101/038224 (2016). PMC5203714 28038678 · DOI
- [22]Schizophrenia Working Group of the Psychiatric Genomics, C. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421– 427, doi: 10.1038/nature13595 (2014). 25056061 PMC4112379 · DOI · Paper page
- [26]Weinberger DR & Levitt P in Schizophrenia 393– 412 (Wiley-Blackwell, 2011).
- [48]Stouffer SAS, E.A.; DeVinney LC; Star SA; Williams RM Jr. The American Soldier, Vol.1: Adjustment during Army Life.. Princeton University Press, Princeton, (1949).
- Authors
- The BrainSeq Consortium, Jaffe, A. E., Straub, R. E., Shin, J. H., Tao, R., Gao, Y., Collado-Torres, L., Kam-Thong, T., Xi, H. S., Quan, J., Chen, Q., Colantuoni, C., Ulrich, W. S., Maher, B. J., Deep-Soboslay, A., Cross, A. J., Brandon, N. J., Leek, J. T., Hyde, T. M., Kleinman, J. E., & Weinberger, D. R.
- Affiliations
- Johns Hopkins University (US)
- Lieber Institute for Brain Development (US)
- F. Hoffmann-La Roche AG (CH)
- Pfizer (United States) (US)
- AstraZeneca (United States) (US)
- Corresponding author
- Jaffe, Andrew E.
- Weinberger, Daniel R.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2018-07-26
- Volume
- 21
- Issue
- 8
- Pages
- 1117-1125
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6438700
- OpenAlex
- W2883175830
- Cited by
- 364
- References
- 55
- Citations by year
- 2026: 28 · 2025: 32 · 2024: 41 · 2023: 49 · 2022: 44 · 2021: 57 · 2020: 58 · 2019: 38 · 2018: 15 · 2017: 2
- FWCI
- 32.82
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Miami (MH101810, MH090936, MH101814, MH101822, MH090937, MH101825, MH090951, MH090948, MH101819, MH101782, DA006227, MH101820, DA033684, N01MH000028, MH090941)
- University of Pennsylvania (phs000424, MH101822)
- Harvard University (MH101782, MH090948)
- University of Chicago (MH101820, MH090951, MH090937, MH101825)
- Broad Institute (HHSN268201000029C)
- Consejo Nacional de Ciencia y Tecnología
- Université de Genève (MH101814, MH090941)
- National Institutes of Health (10XS170, #HHSN261200800001E, HHSN268201000029C, 10XS171, HHSN261200800001C, 5r01mh080405-05, 10ST1035)
- National Institute on Aging (P50AG005138, P01AG002219)
- National Heart, Lung, and Blood Institute (HHSN268201000029C, HHSN261200800001E)
- National Institute of Mental Health (P50MH084053, R01MH101814, R01 MH‐080405, HHSN271201300031C, R01MH093725, R01MH101822, R01MH090937, R01MH101810, P50MH066392, MH101782, HHSN261200800001E, R01MH101782, R01MH075916, MH-090941, R01MH101819, R01MH101820, R01MH085542, R01MH090948, R37MH057881, MH090948, MH101825, R01MH097276, R01MH101825, R01MH090941, MH101819, MH101820, MH090951, N01MH000028, R01MH090936, R01MH090951, R21MH109956, MH101810, MH101822, MH090936, MH101814, MH090937)
- National Institute on Drug Abuse (DA006227, R01DA033684, R01DA006227, DA033684)
- National Human Genome Research Institute (MH101825, HHSN261200800001E)
- NIH Office of the Director (HHSN261200800001E)
- National Cancer Institute (HHSN261200800001E), HHSN268201000029C)
- National Institute of Neurological Disorders and Stroke
- National Institute of Child Health and Human Development
- Common Fund
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- schizophrenia, human brain transcriptome, cortical development, expression quantitative trait loci, alternative splicing, isoform usage, pre- and postnatal development, differentially expressed genes, synaptic genes, treatment effects, gene expression regulation
- MeSH terms
- Adolescent, Adult, Autopsy, Child, Child, Preschool, Chronic Disease, Female, Genotype, Humans, Infant, Male, Pregnancy, Schizophrenia, Genetic Variation, Prefrontal Cortex, Sequence Analysis, RNA, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Databases, Genetic, Transcriptome
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