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Dong, Pengfei; Hoffman, Gabriel E; Apontes, Pasha; Bendl, Jaroslav; Rahman, Samir; Fernando, Michael B; Zeng, Biao; Vicari, James M; Zhang, Wen; Girdhar, Kiran; Townsley, Kayla G; Misir, Ruth; Brennand, Kristen J; Haroutunian, Vahram; Voloudakis, Georgios; Fullard, John F; Roussos, Panos
Nature genetics, 10/2022, Letnik: 54, Številka: 10Journal Article
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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in: SICRIS
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