Journal
NATURE NEUROSCIENCE
Volume 19, Issue 11, Pages 1442-1453Publisher
NATURE PORTFOLIO
DOI: 10.1038/nn.4399
Keywords
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Categories
Funding
- Takeda Pharmaceuticals Company Limited
- F. Hoffman-La Roche Ltd
- VA VISN3 MIRECC
- NIMH Intramural program
- New York Stem Cell Foundation
- Silvio O Conte Center grant [P50MH094268]
- NARSAD
- Stanley Medical Research Institute
- NIMH [R01MH074313, R01AG036836, U01AG046152, R01AG017917, R01AG046170, R01MH109706]
- [R01MH093725-02S1]
- [P50MH066392]
- [R01MH097276]
- [R01MH075916]
- [P50MH096891]
- [P50MH084053-S1]
- [R37MH057881]
- [R37MH057881S1]
- [R01MH085542-S1]
- [U01MH096296-S2]
- [HHSN271201300031C]
- [R01MH101454]
- [R01MH109677]
- [R01AG050986]
- [VA Merit BX002395]
- [R01 AG036836]
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Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource,similar to 20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were <= 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.
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