Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia

被引：66

作者：

Breen, Michael S. ^{[1
,2
,3
]}

Dobbyn, Amanda ^{[2
,4
,5
]}

Lib, Qin ^{[6
]}

Roussos, Panos ^{[1
,2
,5
,7
,8
]}

Hoffman, Gabriel E. ^{[2
,5
,9
]}

Stahl, Eli ^{[1
,2
,5
,9
,10
]}

Chess, Andrew ^{[2
,8
,9
,11
]}

Sklar, Pamela ^{[8
,9
,27
]}

Li, Jin Billy ^{[6
]}

Devlin, Bernie ^{[12
]}

Buxbaum, Joseph D. ^{[1
,2
,3
,8
,13
]}

Akbarian, Schahram ^{[1
,14
]}

Bendl, Jaroslav ^{[1
,5
]}

Brennand, Kristen ^{[1
,5
]}

Brown, Leanne ^{[1
,14
]}

Browne, Andrew ^{[3
]}

Charney, Alexander ^{[1
,5
]}

Couto, Lizette ^{[1
,14
]}

Crawford, Greg ^{[15
]}

Devillers, Olivia ^{[1
,14
]}

Domenici, Enrico ^{[16
]}

Filosi, Michele ^{[16
]}

Flatow, Elie ^{[1
,14
]}

Francoeur, Nancy ^{[5
]}

Fullard, John F. ^{[1
,2
,14
]}

Gil, Sergio Espeso ^{[1
,14
]}

Girdhar, Kiran ^{[1
,5
]}

Gulyas-Kovacs, Attila ^{[11
]}

Gur, Raquel ^{[11
,17
]}

Hahn, Chang-Gyu ^{[18
]}

Haroutunian, Vahram ^{[1
,5
,7
,19
]}

Hauberg, Mads Engel ^{[8
,20
]}

Huckins, Laura ^{[1
,5
]}

Jacobov, Rivky ^{[1
,14
]}

Jiang, Yan ^{[1
,14
]}

Johnson, Jessica S. ^{[1
,5
]}

Kassim, Bibi ^{[1
,14
]}

Kim, Yungil ^{[1
,5
]}

Klei, Lambertus ^{[14
]}

Kramer, Robin ^{[21
]}

Lauria, Mario ^{[22
]}

Lehner, Thomas ^{[22
]}

Lewis, David A. ^{[24
]}

Lipska, Barbara K. ^{[21
]}

Marenco, Stefano ^{[21
]}

Mangravite, Lara M. ^{[25
]}

Montgomery, Kelsey ^{[25
]}

Park, Royce ^{[1
,14
]}

Perumal, Thanneer Malai ^{[25
]}

Peters, Mette A. ^{[25
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Pamela Sklar Div Psychiat Genom, New York, NY 10029 USA

[6] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[7] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN South 2, Bronx, NY USA

[8] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[9] Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA

[10] Broad Inst MIT & Harvard, Med & Populat Genet, Cambridge, MA 02142 USA

[11] Icahn Sch Med Mt Sinai, Dept Cell Dev & Regenerat Biol, New York, NY 10029 USA

[12] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA

[13] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[14] Icahn Sch Med Mt Sinai, Div Psychiat Epigen, New York, NY 10029 USA

[15] Duke Univ, Ctr Genom & Computat Biol, Durham, NC USA

[16] Univ Trento, Ctr Integrat Biol, Lab Neurogen Biomarkers, Trento, Italy

[17] Univ Penn, Dept Psychiat, Neuropsychiat Sect, Perelman Sch Med, Philadelphia, PA 19104 USA

[18] Univ Penn, Dept Psychiat, Neuropsychiat Signaling Program, Perelman Sch Med, Philadelphia, PA 19104 USA

[19] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[20] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[21] NIMH, Human Brain Collect Core, NIH, Bethesda, MD 20892 USA

[22] Univ Trento, Dept Math, Trento, Italy

[23] NIMH, Bethesda, MD 20892 USA

[24] Vanderbilt Univ, Med Ctr, Dept Med Psychiat & Biomed Informat, Nashville, TN USA

[25] Sage Bionetworks, Seattle, WA USA

[26] Vanderbilt Univ, Vanderbilt Genet Inst, Med Ctr, Nashville, TN USA

[27] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[28] Carnegie Mellon Univ, Dept Stat & Data Sci, Pittsburgh, PA 15213 USA

来源：

NATURE NEUROSCIENCE | 2019年 / 22卷 / 09期

关键词：

5-HT2C RECEPTOR; POLYGENIC RISK; CANDIDATE GENE; CHANNELS; TRAFFICKING; ASSOCIATION; COMPLEXITY; SPECTRUM; PACKAGE;

D O I：

10.1038/s41593-019-0463-7

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

RNA editing critically regulates neurodevelopment and normal neuronal function. The global landscape of RNA editing was surveyed across 364 schizophrenia cases and 383 control postmortem brain samples from the CommonMind Consortium, comprising two regions: dorsolateral prefrontal cortex and anterior cingulate cortex. In schizophrenia, RNA editing sites in genes encoding AMPA-type glutamate receptors and postsynaptic density proteins were less edited, whereas those encoding translation initiation machinery were edited more. These sites replicate between brain regions, map to 3'-untranslated regions and intronic regions, share common sequence motifs and overlap with binding sites for RNA-binding proteins crucial for neurodevelopment. These findings cross-validate in hundreds of non-overlapping dorsolateral prefrontal cortex samples. Furthermore, similar to 30% of RNA editing sites associate with cis-regulatory variants (editing quantitative trait loci or edQTLs). Finemapping edQTLs with schizophrenia risk loci revealed co-localization of eleven edQTLs with six loci. The findings demonstrate widespread altered RNA editing in schizophrenia and its genetic regulation, and suggest a causal and mechanistic role of RNA editing in schizophrenia neuropathology.

引用

页码：1402 / +

页数：14

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