Gene expression elucidates functional impact of polygenic risk for schizophrenia.

Autor: Fromer M; 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., Roussos P; 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., Sieberts SK; Systems Biology, Sage Bionetworks, Seattle, Washington, USA., Johnson JS; Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Kavanagh DH; 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., Perumal TM; Systems Biology, Sage Bionetworks, Seattle, Washington, USA., Ruderfer DM; 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., Oh EC; Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.; Department of Neurology, Duke University, Durham, North Carolina, USA., Topol A; Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Shah HR; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Klei LL; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Kramer R; Human Brain Collection Core, National Institutes of Health, NIMH, Bethesda, Maryland, USA., Pinto D; 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., Gümüş ZH; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Cicek AE; Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA., Dang KK; Systems Biology, Sage Bionetworks, Seattle, Washington, USA., Browne A; 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., Lu C; Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA., Xie L; Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA., Readhead B; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Stahl EA; 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., Xiao J; Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA., Parvizi M; Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA., Hamamsy T; 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., Fullard JF; Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Wang YC; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Mahajan MC; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Derry JM; Systems Biology, Sage Bionetworks, Seattle, Washington, USA., Dudley JT; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Hemby SE; Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA., Logsdon BA; Systems Biology, Sage Bionetworks, Seattle, Washington, USA., Talbot K; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA., Raj T; 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., Bennett DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA., De Jager PL; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA., Zhu J; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Zhang B; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Sullivan PF; 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., Chess A; 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., Purcell SM; 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., Shinobu LA; CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan., Mangravite LM; Systems Biology, Sage Bionetworks, Seattle, Washington, USA., Toyoshiba H; Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan., Gur RE; Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Hahn CG; Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Lewis DA; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Haroutunian V; 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., Peters MA; Systems Biology, Sage Bionetworks, Seattle, Washington, USA., Lipska BK; Human Brain Collection Core, National Institutes of Health, NIMH, Bethesda, Maryland, USA., Buxbaum JD; 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., Schadt EE; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Hirai K; CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan., Roeder K; Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.; Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA., Brennand KJ; 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., Katsanis N; Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.; Department of Cell Biology and Pediatrics, Duke University, Durham, North Carolina, USA., Domenici E; Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy., Devlin B; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Sklar P; 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.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2016 Nov; Vol. 19 (11), pp. 1442-1453. Date of Electronic Publication: 2016 Sep 26.
DOI: 10.1038/nn.4399
Abstrakt: 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.
Databáze: MEDLINE