Gene expression elucidates functional impact of polygenic risk for schizophrenia.
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.
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Menachem
0000-0003-3749-4342
M
Fromer
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Psychiatry, JJ Peters Virginia Medical Center, Bronx, New York, USA.
Panos
P
Roussos
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
Solveig K
SK
Sieberts
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Jessica S
JS
Johnson
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
David H
DH
Kavanagh
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
Thanneer M
TM
Perumal
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Douglas M
DM
Ruderfer
Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.|Department of Neurology, Duke University, Durham, North Carolina, USA.
Edwin C
EC
Oh
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Aaron
A
Topol
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Hardik R
HR
Shah
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Lambertus L
LL
Klei
Human Brain Collection Core, National Institutes of Health, NIMH, Bethesda, Maryland, USA.
Robin
R
Kramer
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Dalila
0000-0002-8769-0846
D
Pinto
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Zeynep H
ZH
Gümüş
Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
A Ercument
AE
Cicek
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
Kristen K
KK
Dang
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Andrew
A
Browne
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
Cong
C
Lu
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
Lu
L
Xie
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ben
B
Readhead
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Eli A
EA
Stahl
Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.
Jianqiu
J
Xiao
Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.
Mahsa
M
Parvizi
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Tymor
T
Hamamsy
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
John F
JF
Fullard
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ying-Chih
YC
Wang
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Milind C
MC
Mahajan
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
Jonathan M J
JM
Derry
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Joel T
JT
Dudley
Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA.
Scott E
SE
Hemby
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
Benjamin A
0000-0002-0572-2569
BA
Logsdon
Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Konrad
K
Talbot
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Towfique
T
Raj
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
David A
DA
Bennett
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Philip L
PL
De Jager
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Jun
J
Zhu
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Bin
B
Zhang
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Patrick F
0000-0002-6619-873X
PF
Sullivan
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Andrew
A
Chess
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Shaun M
SM
Purcell
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Leslie A
LA
Shinobu
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
Lara M
0000-0001-7841-3612
LM
Mangravite
Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Hiroyoshi
H
Toyoshiba
Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Raquel E
RE
Gur
Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Chang-Gyu
CG
Hahn
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
David A
DA
Lewis
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Psychiatry, JJ Peters Virginia Medical Center, Bronx, New York, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Vahram
V
Haroutunian
Systems Biology, Sage Bionetworks, Seattle, Washington, USA.
Mette A
MA
Peters
Human Brain Collection Core, National Institutes of Health, NIMH, Bethesda, Maryland, USA.
Barbara K
BK
Lipska
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Joseph D
JD
Buxbaum
Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Eric E
EE
Schadt
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Keisuke
K
Hirai
Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.|Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
Kathryn
K
Roeder
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Kristen J
KJ
Brennand
Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.|Department of Cell Biology and Pediatrics, Duke University, Durham, North Carolina, USA.
Nicholas
N
Katsanis
Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Enrico
E
Domenici
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Bernie
B
Devlin
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Pamela
P
Sklar
D001921:Brain / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*
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