期刊
NATURE GENETICS
卷 54, 期 10, 页码 1493-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01170-4
关键词
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资金
- Takeda Pharmaceuticals Company Limited
- F. Hoffman-La Roche Ltd
- NIH through the NIMH Intramural Research Program (IRP) [R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, AG02219, AG05138, MH06692, R01MH110921, R01MH109677, R01MH109897, U01MH103392, U01MH116442, ZIC MH002903, HHSN271201300031C]
- NIA through NIH grants [R01-AG067025, R01-AG065582, R01-AG050986]
- NIMH through NIH [R01-MH110921, U01-MH116442, R01-MH125246, R01-MH106056, R01-MH109897, R01-MH121074]
- Veterans Affairs Merit grant [BX002395]
- NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation [29683, 26313, 27209]
This study characterizes the gene-enhancer regulome and regulatory mechanisms in the human brain, shedding light on the role of enhancer function in neuropsychiatric diseases. Enhancer eQTLs are found to mediate a substantial portion of neuropsychiatric trait heritability.
Analyses of population-level variation in gene and enhancer expression in the human brain characterize the gene-enhancer regulome and the regulatory mechanisms of transcribed enhancers in neuropsychiatric diseases. Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain. Besides regulating tissue-specific and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. By jointly analyzing large-scale cell-type-specific transcriptome and regulome data, we cataloged 30,795 neuronal and 23,265 non-neuronal candidate transcribed enhancers. Examination of the transcriptome in 1,382 brain samples identified robust expression of transcribed enhancers. We explored gene-enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified expression quantitative trait loci (eQTLs) for both genes and enhancers and found that enhancer eQTLs mediate a substantial fraction of neuropsychiatric trait heritability. Inclusion of enhancer eQTLs in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the gene-enhancer regulome and genetic mechanisms in the human cortex in both healthy and diseased states.
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