Gene expression elucidates functional impact of polygenic risk for schizophrenia

Menachem Fromer, Panos Roussos, Solveig K. Sieberts, Jessica S. Johnson, David H. Kavanagh, Thanneer M. Perumal, Douglas M. Ruderfer, Edwin C. Oh, Aaron Topol, Hardik R. Shah, Lambertus L. Klei, Robin Kramer, Dalila Pinto, Zeynep H. Gümüş, A. Ercument Cicek, Kristen K. Dang, Andrew Browne, Cong Lu, Lu Xie, Benjamin ReadheadEli A. Stahl, Jianqiu Xiao, Mahsa Parvizi, Tymor Hamamsy, John F. Fullard, Ying Chih Wang, Milind C. Mahajan, Jonathan M.J. Derry, Joel T. Dudley, Scott E. Hemby, Benjamin A. Logsdon, Konrad Talbot, Towfique Raj, David A. Bennett, Philip L. De Jager, Jun Zhu, Bin Zhang, Patrick F. Sullivan, Andrew Chess, Shaun M. Purcell, Leslie A. Shinobu, Lara M. Mangravite, Hiroyoshi Toyoshiba, Raquel E. Gur, Chang Gyu Hahn, David A. Lewis, Vahram Haroutunian, Mette A. Peters, Barbara K. Lipska, Joseph D. Buxbaum, Eric E. Schadt, Keisuke Hirai, Kathryn Roeder, Kristen J. Brennand, Nicholas Katsanis, Enrico Domenici, Bernie Devlin, Pamela Sklar

Research output: Contribution to journalReview article

248 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1442-1453
Number of pages12
JournalNature Neuroscience
Volume19
Issue number11
DOIs
StatePublished - Oct 26 2016
Externally publishedYes

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Schizophrenia
Gene Expression
Furin
Genetic Loci
Brain Diseases
Zebrafish
Prefrontal Cortex
Genes
Stem Cells
RNA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Fromer, M., Roussos, P., Sieberts, S. K., Johnson, J. S., Kavanagh, D. H., Perumal, T. M., ... Sklar, P. (2016). Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience, 19(11), 1442-1453. https://doi.org/10.1038/nn.4399

Gene expression elucidates functional impact of polygenic risk for schizophrenia. / Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K.; Johnson, Jessica S.; Kavanagh, David H.; Perumal, Thanneer M.; Ruderfer, Douglas M.; Oh, Edwin C.; Topol, Aaron; Shah, Hardik R.; Klei, Lambertus L.; Kramer, Robin; Pinto, Dalila; Gümüş, Zeynep H.; Cicek, A. Ercument; Dang, Kristen K.; Browne, Andrew; Lu, Cong; Xie, Lu; Readhead, Benjamin; Stahl, Eli A.; Xiao, Jianqiu; Parvizi, Mahsa; Hamamsy, Tymor; Fullard, John F.; Wang, Ying Chih; Mahajan, Milind C.; Derry, Jonathan M.J.; Dudley, Joel T.; Hemby, Scott E.; Logsdon, Benjamin A.; Talbot, Konrad; Raj, Towfique; Bennett, David A.; De Jager, Philip L.; Zhu, Jun; Zhang, Bin; Sullivan, Patrick F.; Chess, Andrew; Purcell, Shaun M.; Shinobu, Leslie A.; Mangravite, Lara M.; Toyoshiba, Hiroyoshi; Gur, Raquel E.; Hahn, Chang Gyu; Lewis, David A.; Haroutunian, Vahram; Peters, Mette A.; Lipska, Barbara K.; Buxbaum, Joseph D.; Schadt, Eric E.; Hirai, Keisuke; Roeder, Kathryn; Brennand, Kristen J.; Katsanis, Nicholas; Domenici, Enrico; Devlin, Bernie; Sklar, Pamela.

In: Nature Neuroscience, Vol. 19, No. 11, 26.10.2016, p. 1442-1453.

Research output: Contribution to journalReview article

Fromer, M, Roussos, P, Sieberts, SK, Johnson, JS, Kavanagh, DH, Perumal, TM, Ruderfer, DM, Oh, EC, Topol, A, Shah, HR, Klei, LL, Kramer, R, Pinto, D, Gümüş, ZH, Cicek, AE, Dang, KK, Browne, A, Lu, C, Xie, L, Readhead, B, Stahl, EA, Xiao, J, Parvizi, M, Hamamsy, T, Fullard, JF, Wang, YC, Mahajan, MC, Derry, JMJ, Dudley, JT, Hemby, SE, Logsdon, BA, Talbot, K, Raj, T, Bennett, DA, De Jager, PL, Zhu, J, Zhang, B, Sullivan, PF, Chess, A, Purcell, SM, Shinobu, LA, Mangravite, LM, Toyoshiba, H, Gur, RE, Hahn, CG, Lewis, DA, Haroutunian, V, Peters, MA, Lipska, BK, Buxbaum, JD, Schadt, EE, Hirai, K, Roeder, K, Brennand, KJ, Katsanis, N, Domenici, E, Devlin, B & Sklar, P 2016, 'Gene expression elucidates functional impact of polygenic risk for schizophrenia', Nature Neuroscience, vol. 19, no. 11, pp. 1442-1453. https://doi.org/10.1038/nn.4399
Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience. 2016 Oct 26;19(11):1442-1453. https://doi.org/10.1038/nn.4399
Fromer, Menachem ; Roussos, Panos ; Sieberts, Solveig K. ; Johnson, Jessica S. ; Kavanagh, David H. ; Perumal, Thanneer M. ; Ruderfer, Douglas M. ; Oh, Edwin C. ; Topol, Aaron ; Shah, Hardik R. ; Klei, Lambertus L. ; Kramer, Robin ; Pinto, Dalila ; Gümüş, Zeynep H. ; Cicek, A. Ercument ; Dang, Kristen K. ; Browne, Andrew ; Lu, Cong ; Xie, Lu ; Readhead, Benjamin ; Stahl, Eli A. ; Xiao, Jianqiu ; Parvizi, Mahsa ; Hamamsy, Tymor ; Fullard, John F. ; Wang, Ying Chih ; Mahajan, Milind C. ; Derry, Jonathan M.J. ; Dudley, Joel T. ; Hemby, Scott E. ; Logsdon, Benjamin A. ; Talbot, Konrad ; Raj, Towfique ; Bennett, David A. ; De Jager, Philip L. ; Zhu, Jun ; Zhang, Bin ; Sullivan, Patrick F. ; Chess, Andrew ; Purcell, Shaun M. ; Shinobu, Leslie A. ; Mangravite, Lara M. ; Toyoshiba, Hiroyoshi ; Gur, Raquel E. ; Hahn, Chang Gyu ; Lewis, David A. ; Haroutunian, Vahram ; Peters, Mette A. ; Lipska, Barbara K. ; Buxbaum, Joseph D. ; Schadt, Eric E. ; Hirai, Keisuke ; Roeder, Kathryn ; Brennand, Kristen J. ; Katsanis, Nicholas ; Domenici, Enrico ; Devlin, Bernie ; Sklar, Pamela. / Gene expression elucidates functional impact of polygenic risk for schizophrenia. In: Nature Neuroscience. 2016 ; Vol. 19, No. 11. pp. 1442-1453.
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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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AU - Shah, Hardik R.

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AU - Readhead, Benjamin

AU - Stahl, Eli A.

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AU - Hamamsy, Tymor

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