Abstract

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.

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Acknowledgements

We acknowledge M. Gandal, B. van de Geijn, A. Ko, P.-R. Loh, L. O’Connor, P. Pajukanta, and N. Zaitlen for helpful discussions. This research was funded by NIH grants F32GM106584 (A.G.), R01GM105857 (A.L.P.), R01MH109978 (A.L.P.), R01MH107649 (B.M.N.), R01MH105472 (G.E.C. and P.F.S.), R01HG009120 (B.P.), U01 MH103339-03S2 (D.H.G.), and R01 MH110927-02 (D.H.G.). H.K.F. was supported by the Fannie and John Hertz Foundation. The project described was also supported by award no. T32GM007753 from the National Institute of General Medical Sciences.This study was supported by a P50MH094268 grant (to N.K.). N.K. is suported as a distinguished Jean and George Brumley Professor. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. We are grateful to the CommonMind Consortium and the PsychENCODE Consortium for making data publicly and readily available. Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited; F. Hoffman-La Roche Ltd.; and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, R37MH057881S1, HHSN271201300031C, AG02219, AG05138, and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimers Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories, and the NIMH Human Brain Collection Core. CMC Leadership: P. Sklar, J. Buxbaum (Icahn School of Medicine at Mount Sinai), B. Devlin, D. Lewis (University of Pittsburgh), R. Gur, C.-G. Hahn (University of Pennsylvania), K. Hirai, H. Toyoshiba (Takeda Pharmaceuticals Company Limited), E. Domenici, L. Essioux (F. Hoffman-La Roche Ltd.), L. Mangravite, M. Peters (Sage Bionetworks), T. Lehner, and B. Lipska (NIMH). Data were generated as part of the PsychENCODE Consortium, supported by U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to S. Akbarian (Icahn School of Medicine at Mount Sinai), G. Crawford (Duke), S. Dracheva (Icahn School of Medicine at Mount Sinai), P. Farnham (USC), M. Gerstein (Yale), D. Geschwind (UCLA), T. M. Hyde (LIBD), A. Jaffe (LIBD), J. A. Knowles (USC), C. Liu (UIC), D. Pinto (Icahn School of Medicine at Mount Sinai), N. Sestan (Yale), P. Sklar (Icahn School of Medicine at Mount Sinai), M. State (UCSF), P. Sullivan (UNC), F. Vaccarino (Yale), S. Weissman (Yale), K. White (University of Chicago), and P. Zandi (JHU).

Author information

Author notes

  1. A full list of members and affiliations appears in the Supplementary Note

  2. These authors jointly supervised this work: Bogdan Pasaniuc and Alkes L. Price.

Affiliations

  1. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Alexander Gusev
    • , Hilary K. Finucane
    •  & Alkes L. Price
  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Alexander Gusev
    • , Hilary K. Finucane
    • , Benjamin M. Neale
    •  & Alkes L. Price
  3. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    • Alexander Gusev
  4. Department of Pathology and Lab Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Nicholas Mancuso
    •  & Bogdan Pasaniuc
  5. Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    • Hyejung Won
    •  & Daniel H. Geschwind
  6. Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA

    • Maria Kousi
    •  & Nicholas Katsanis
  7. Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Hilary K. Finucane
  8. Department of Computer Science, Harvard University, Cambridge, MA, USA

    • Yakir Reshef
  9. Center for Genomic and Computational Biology, Duke University, Durham, NC, USA

    • Lingyun Song
    • , Alexias Safi
    •  & Gregory E. Crawford
  10. Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA

    • Lingyun Song
    • , Alexias Safi
    •  & Gregory E. Crawford
  11. Department of Genetics, Harvard Medical School, Boston, MA, USA

    • Steven McCarroll
  12. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Steven McCarroll
    •  & Benjamin M. Neale
  13. Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Benjamin M. Neale
  14. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Hyejung Won
    • , Roel A. Ophoff
    •  & Daniel H. Geschwind
  15. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands

    • Roel A. Ophoff
  16. MRC Centre for Psychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    • Michael C. O’Donovan
  17. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, CA, USA

    • Daniel H. Geschwind
    •  & Bogdan Pasaniuc
  18. Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Daniel H. Geschwind
  19. Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA

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

    • Patrick F. Sullivan

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Consortia

  1. Schizophrenia Working Group of the Psychiatric Genomics Consortium

    Contributions

    A.G., B.P., and A.L.P. designed the study. A.G., N.M., H.W., H.K.F., and Y.R. conducted analyses. M.K., L.S., A.S., G.E.C., D.H.G., N.K., and P.F.S. conducted and supervised experiments. The Psychiatric Genomics Consortium, S.M., B.M.N., R.A.O., M.C.O., and P.F.S. collected the data. A.G., B.P., and A.L.P. wrote the paper.

    Competing interests

    The authors declare no competing interests.

    Corresponding authors

    Correspondence to Alexander Gusev or Bogdan Pasaniuc or Alkes L. Price.

    Supplementary information

    1. Supplementary Text and Figures

      Supplementary Figures 1–39, Supplementary Tables 1, 2, 4–18 and 20–25, and Supplementary Note

    2. Life Sciences Reporting Summary

    3. Supplementary Tables 3 and 19

      Supplementary Tables 3 and 19