Article | Published:

Gene expression elucidates functional impact of polygenic risk for schizophrenia

Nature Neuroscience volume 19, pages 14421453 (2016) | Download Citation

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.

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Acknowledgements

We thank the patients and families who donated material for these studies. We thank T. Lehner for his early and inspirational ideas about this project, as well as organizational and intellectual support. We thank X. He for discussions regarding Sherlock, J. Scarpa for help running and interpreting WGCNA, L. Essioux for support in establishing and managing interactions with the Consortium, and A. Bertolino and A. Ghosh for continuous encouragement. Data and results were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd; grants R01MH093725-02S1 (J.D.B.), P50MH066392 (J.D.B.), R01MH097276 (P.S., E.E.S.), R01MH075916 (C.-G.H.), P50MH096891 C.-G.H., REG, P50MH084053-S1 (D.A.L.), R37MH057881 (B.D.), R37MH057881S1 (B.D.), R01MH085542-S1 (P.S.), U01MH096296-S2 (P.S.), HHSN271201300031C (V.H.), VA VISN3 MIRECC (V.H.), P50MH066392 (J.D.B.), NIMH Intramural program (B.K.L.), R01MH101454 (K.J.B.), R01MH109677 (P.R.), R01AG050986 (P.R.), VA Merit BX002395 (P.R.) and R01 AG036836 (P.D.H.); New York Stem Cell Foundation (K.J.B.); the Silvio O Conte Center grant P50MH094268 (N.K.); NARSAD (E.C.O.) and NARSAD Young Investigator (D.M.R., P.R., E.A.S.); the Stanley Medical Research Institute for Funding for Non-Human Primate Research; and NIMH grants R01MH074313 (S.E.H.); R01AG036836, U01AG046152 and R01AG017917 (D.A.B. and P.I.D.J.); R01AG046170 (E.S.S., B.Z., J.Z., and P.R.); and R01MH109706 (E.C.O.). Brain tissues for the study were obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer's Disease Core Center, the University of Pittsburgh Brain Tissue Donation Program, the NIMH Human Brain Collection Core and Wake Forest University. CMC Leadership: P. Sklar and J.D. Buxbaum (Icahn School of Medicine at Mount Sinai), B. Devlin and D.A. Lewis (University of Pittsburgh), R.E. Gur and C.-G. Hahn (University of Pennsylvania), K. Hirai and H. Toyoshiba (Takeda Pharmaceuticals Company Limited), E. Domenici and L. Essioux (F. Hoffman-La Roche Ltd), L.M. Mangravite and M.A. Peters (Sage Bionetworks), and T. Lehner and B.K. Lipska (NIMH).

Author information

Author notes

    • Menachem Fromer
    • , Panos Roussos
    •  & Solveig K Sieberts

    These authors contributed equally to this work.

    • Bernie Devlin
    •  & Pamela Sklar

    These authors jointly directed this work.

Affiliations

  1. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Menachem Fromer
    • , Panos Roussos
    • , Jessica S Johnson
    • , David H Kavanagh
    • , Douglas M Ruderfer
    • , Aaron Topol
    • , Dalila Pinto
    • , Eli A Stahl
    • , Tymor Hamamsy
    • , John F Fullard
    • , Shaun M Purcell
    • , Vahram Haroutunian
    • , Joseph D Buxbaum
    • , Kristen J Brennand
    •  & Pamela Sklar
  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.

    • Menachem Fromer
    • , Panos Roussos
    • , David H Kavanagh
    • , Douglas M Ruderfer
    • , Hardik R Shah
    • , Dalila Pinto
    • , Zeynep H Gümüş
    • , Ben Readhead
    • , Eli A Stahl
    • , Tymor Hamamsy
    • , Ying-Chih Wang
    • , Milind C Mahajan
    • , Joel T Dudley
    • , Towfique Raj
    • , Jun Zhu
    • , Bin Zhang
    • , Andrew Chess
    • , Shaun M Purcell
    • , Eric E Schadt
    •  & Pamela Sklar
  3. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Panos Roussos
    • , Dalila Pinto
    • , Andrew Browne
    • , Andrew Chess
    • , Joseph D Buxbaum
    • , Kristen J Brennand
    •  & Pamela Sklar
  4. Psychiatry, JJ Peters Virginia Medical Center, Bronx, New York, USA.

    • Panos Roussos
    •  & Vahram Haroutunian
  5. Systems Biology, Sage Bionetworks, Seattle, Washington, USA.

    • Solveig K Sieberts
    • , Thanneer M Perumal
    • , Kristen K Dang
    • , Jonathan M J Derry
    • , Benjamin A Logsdon
    • , Lara M Mangravite
    •  & Mette A Peters
  6. Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.

    • Edwin C Oh
    • , Jianqiu Xiao
    • , Mahsa Parvizi
    •  & Nicholas Katsanis
  7. Department of Neurology, Duke University, Durham, North Carolina, USA.

    • Edwin C Oh
  8. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Lambertus L Klei
    • , David A Lewis
    •  & Bernie Devlin
  9. Human Brain Collection Core, National Institutes of Health, NIMH, Bethesda, Maryland, USA.

    • Robin Kramer
    •  & Barbara K Lipska
  10. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Dalila Pinto
    • , Andrew Browne
    •  & Joseph D Buxbaum
  11. Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

    • A Ercument Cicek
    •  & Kathryn Roeder
  12. Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

    • Cong Lu
    • , Lu Xie
    •  & Kathryn Roeder
  13. Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA.

    • Scott E Hemby
  14. Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Konrad Talbot
  15. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Towfique Raj
    • , Vahram Haroutunian
    •  & Kristen J Brennand
  16. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Towfique Raj
    •  & Philip L De Jager
  17. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

    • David A Bennett
  18. Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Philip L De Jager
  19. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Patrick F Sullivan
  20. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Patrick F Sullivan
  21. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Andrew Chess
  22. CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.

    • Leslie A Shinobu
    •  & Keisuke Hirai
  23. Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.

    • Hiroyoshi Toyoshiba
  24. Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Raquel E Gur
  25. Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Chang-Gyu Hahn
  26. Department of Cell Biology and Pediatrics, Duke University, Durham, North Carolina, USA.

    • Nicholas Katsanis
  27. Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.

    • Enrico Domenici
  28. Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Bernie Devlin

Authors

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Contributions

P.R., J.S.J., K.T., R.E.G., C.-G.H., D.A.L., V.H., B.K.L. and J.D.B. contributed to sample collection. S.E.H. contributed monkey brain tissue and P.F.S. contributed mouse data. M.F., P.R., S.K.S., D.H.K., T.M.P., D.M.R., K.K.D., E.C.O., A.T., T.C., M.A.P., E.D., B.D. and P.S. contributed to the writing of this manuscript. M.F., P.R., S.K.S., H.R.S., D.M.R., K.K.D., M.C.M., J.M.J.D., A.C., S.M.P., L.A.S., L.M.M., H.T., D.A.L., M.A.P., J.D.B., E.E.S., K.H., K.J.B., N.K., B.D. and P.S. contributed to experimental and study design and planning analytical strategies. L.A.S., H.T., D.A.L., B.K.L., J.D.B., E.E.S., K.H., E.D., B.D. and P.S. contributed the funding of this work. M.F., P.R., S.K.S., J.S.J., D.H.K., T.M.P., D.M.R., H.R.S., L.L.K., R.K., D.P., Z.H.G., A.E.C., L.X., A.C., K.K.D., A.B., C.L., B.R., E.A.S., T.H., J.F.F., Y.-C.W., J.T.D., B.A.L., T.R., J.Z., B.Z., P.F.S., S.M.P., E.E.S., K.R., E.D., B.D. and P.S. contributed to data analyses. E.C.O., A.T., J.X., M.P., K.J.B. and N.K. contributed to the model system experiments. T.R., D.A.B., P.L.D.J. contributed the ROS/MAP data. A.C., L.A.S., L.M.M., H.T., R.E.G., C.-G.H., D.A.L., M.A.P., B.K.L., J.D.B., K.H., E.E.S., E.D., B.D. and P.S. contributed to the management and leadership of phase 1 of the CommonMind Consortium.

Competing interests

E. Dominici was an employee of F. Hoffmann-La Roche for the first portion of the study and later served as a consultant to Roche in the area of genetic biomarkers. H. Toyoshiba and K. Hirai are employees of Takeda Pharmaceutical Company Limited and L.A. Shinobu is a former employee. D.A.L. currently receives investigator-initiated research support from Pfizer and from 2012 to 2014 served as a consultant in the areas of target identification and validation and new compound development to Autifony, Bristol-Myers Squibb, Concert Pharmaceuticals and Sunovion. M. Fromer was an employee of Mount Sinai until April 2016; he is now an employee of Google Verily.

Corresponding author

Correspondence to Pamela Sklar.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12, Supplementary Information, and Supplementary Tables 1–3

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Data File 1

    Published post-mortem genome-wide differential gene expression studies in schizophrenia

  2. 2.

    Supplementary Data File 2

    Summary of regions with genes ranked highly by Sherlock; Genes with max-eQTL ranked as credible by PGC SCZ2 GWAS data; Isoforms with max-eQTL ranked as credible by PGC SCZ2 GWAS data

  3. 3.

    Supplementary Data File 3

    Differentially expressed genes; Differentially expressed isoforms; Comparison of CMC and HBCC

  4. 4.

    Supplementary Data File 4

    Enrichment of differential expression in hypothesis-driven and hypothesis-free gene sets

  5. 5.

    Supplementary Data File 5

    Module assignments and connectivity values in the control network; Module assignments and connectivity values in the schizophrenia network

  6. 6.

    Supplementary Data File 6

    Overlap of differentially expressed genes with modules in the control network; Overlap of differentially expressed genes with modules in the case network

  7. 7.

    Supplementary Data File 7

    Geneset enrichment for modules in the control network; Geneset enrichment for modules in the schizophrenia network

About this article

Publication history

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Accepted

Published

DOI

https://doi.org/10.1038/nn.4399

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