Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights

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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Fig. 1: Schematic of the TWAS approach.
Fig. 2: Schizophrenia TWAS associations and polygenic effects.
Fig. 3: Chromatin TWAS associations compared with top eSNP–cQTL associations.
Fig. 4: Chromatin and schizophrenia TWAS association at PPP2R3C.
Fig. 5: Chromatin and schizophrenia TWAS association at KLC1.
Fig. 6: Suppression of endogenous mapk3 rescues the microcephaly and neuronal-proliferation phenotypes induced by overexpression of wild-type KCTD13.

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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).

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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.

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

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Gusev, A., Mancuso, N., Won, H. et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet 50, 538–548 (2018). https://doi.org/10.1038/s41588-018-0092-1

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