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Nat Neurosci. 2016 Nov;19(11):1442-1453. doi: 10.1038/nn.4399. Epub 2016 Sep 26.

Gene expression elucidates functional impact of polygenic risk for schizophrenia.

Author information

1
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
Psychiatry, JJ Peters Virginia Medical Center, Bronx, New York, USA.
5
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
6
Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.
7
Department of Neurology, Duke University, Durham, North Carolina, USA.
8
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
9
Human Brain Collection Core, National Institutes of Health, NIMH, Bethesda, Maryland, USA.
10
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
11
Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
12
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
13
Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA.
14
Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
15
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
16
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
17
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
18
Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
19
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
20
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
21
Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
22
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
23
Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
24
Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
25
Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
26
Department of Cell Biology and Pediatrics, Duke University, Durham, North Carolina, USA.
27
Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
28
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Abstract

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, ∼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.

Comment in

PMID:
27668389
PMCID:
PMC5083142
DOI:
10.1038/nn.4399
[Indexed for MEDLINE]
Free PMC Article

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