期刊
NATURE NEUROSCIENCE
卷 21, 期 8, 页码 1117-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-018-0197-y
关键词
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资金
- Lieber Institute for Brain Development
- Maltz Research Laboratories
- NIH [R21MH109956]
- Consejo Nacional de Ciencia y Tecnologia Mexico [351535]
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts [10X5170, 10X5171, X105172]
- Laboratory, Data Analysis, and Coordinating Center (LDACC) [HHSN268201000029C]
- SAIC-F subcontract [105T1035]
- SAIC-F [HHSN261200800001E]
- Takeda Pharmaceuticals Company Limited
- F. Hoffman-La Roche Ltd
- NIH grants [R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, R01-MH-075916, P50M096891, P50MH08405351, R37MH057881, R37MH05788151, HHSN271201300031C, AG02219, AG05138, MH06692]
- [DA006227]
- [DA033684]
- [N01MH000028]
- [MH090941]
- [MH101814]
- [MH090951]
- [MH090937]
- [MH101820]
- [MH101825]
- [MH090936]
- [MH101819]
- [MH090948]
- [MH101782]
- [MH101810]
- [MH101822]
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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