Gene expression elucidates functional impact of polygenic risk for schizophrenia

被引：757

作者：

Fromer, Menachem ^{[1
,2
]}

Roussos, Panos ^{[1
,2
,3
,4
]}

Sieberts, Solveig K. ^{[5
]}

Johnson, Jessica S. ^{[1
]}

Kavanagh, David H. ^{[1
,2
]}

Perumal, Thanneer M. ^{[5
]}

Ruderfer, Douglas M. ^{[1
,2
]}

Oh, Edwin C. ^{[6
,7
]}

Topol, Aaron ^{[1
]}

Shah, Hardik R. ^{[2
]}

Klei, Lambertus L. ^{[8
]}

Kramer, Robin ^{[9
]}

Pinto, Dalila ^{[1
,2
,10
]}

Gumus, Zeynep H. ^{[2
]}

Cicek, A. Ercument ^{[11
]}

Dang, Kristen K. ^{[5
]}

Browne, Andrew ^{[1
,2
]}

Lu, Cong ^{[12
]}

Xie, Lu ^{[8
]}

Readhead, Ben ^{[2
]}

Stahl, Eli A. ^{[1
,2
]}

Xiao, Jianqiu

Parvizi, Mahsa ^{[6
]}

Hamamsy, Tymor ^{[1
,2
]}

Fullard, John F. ^{[1
]}

Wang, Ying-Chih ^{[2
]}

Mahajan, Milind C. ^{[2
]}

Derry, Jonathan M. J. ^{[5
]}

Dudley, Joel T. ^{[2
]}

Hemby, Scott E. ^{[13
]}

Logsdon, Benjamin A. ^{[5
]}

Talbot, Konrad ^{[14
]}

Raj, Towfique ^{[2
,15
,16
]}

Bennett, David A. ^{[17
]}

De Jager, Philip L. ^{[16
,18
,19
]}

Zhu, Jun ^{[2
]}

Zhang, Bin ^{[2
]}

Sullivan, Patrick F. ^{[20
,21
]}

Chess, Andrew ^{[2
,3
,22
]}

Purcell, Shaun M. ^{[1
,2
]}

Shinobu, Leslie A. ^{[23
]}

Mangravite, Lara M. ^{[5
]}

Toyoshiba, Hiroyoshi ^{[24
]}

Gur, Raquel E. ^{[25
]}

Hahn, Chang-Gyu ^{[26
]}

Lewis, David A. ^{[8
]}

Haroutunian, Vahram ^{[1
,4
,15
]}

Peters, Mette A. ^{[5
]}

Lipska, Barbara K. ^{[9
]}

Buxbaum, Joseph D. ^{[1
,3
,10
]}

机构：

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

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

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

[4] JJ Peters Virginia Med Ctr, Psychiat, Bronx, NY USA

[5] Sage Bionetworks, Syst Biol, Seattle, WA USA

[6] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA

[7] Duke Univ, Dept Neurol, Durham, NC USA

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

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

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

[11] Carnegie Mellon Univ, Sch Comp Sci, Dept Computat Biol, Pittsburgh, PA 15213 USA

[12] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

[13] High Point Univ, Fred Wilson Sch Pharm, Dept Basic Pharmaceut Sci, High Point, NC USA

[14] Cedars Sinai Med Ctr, Dept Neurosurg, Los Angeles, CA 90048 USA

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

[16] Broad Inst MIT & Harvard, Cambridge, MA USA

[17] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[18] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA

[19] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA

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

[21] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

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

[23] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, CNS Drug Discovery Unit, Fujisawa, Kanagawa, Japan

[24] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Integrated Technol Res Labs, Fujisawa, Kanagawa, Japan

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

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

[27] Duke Univ, Dept Cell Biol & Pediat, Durham, NC USA

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

[29] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA

来源：

NATURE NEUROSCIENCE | 2016年 / 19卷 / 11期

关键词：

TRANSCRIPTOMIC ANALYSIS; PREFRONTAL CORTEX; MUTATIONS; METAANALYSIS; PHENOTYPES; NETWORKS;

D O I：

10.1038/nn.4399

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1442 / 1453

页数：12

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