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; Ben Readhead; Eli 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

doi:10.1038/nn.4399

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, Ben 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 journal › Review article › peer-review

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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.

Original language	English (US)
Pages (from-to)	1442-1453
Number of pages	12
Journal	Nature Neuroscience
Volume	19
Issue number	11
DOIs	https://doi.org/10.1038/nn.4399
State	Published - Oct 26 2016
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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Fromer, M., Roussos, P., Sieberts, S. K., Johnson, J. S., Kavanagh, D. H., Perumal, T. M., Ruderfer, D. M., Oh, E. C., Topol, A., Shah, H. R., Klei, L. L., Kramer, R., Pinto, D., Gümüş, Z. H., Cicek, A. E., Dang, K. K., Browne, A., Lu, C., Xie, L., ... 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

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

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title = "Gene expression elucidates functional impact of polygenic risk for schizophrenia",

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.",

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

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AU - Kavanagh, David H.

AU - Perumal, Thanneer M.

AU - Ruderfer, Douglas M.

AU - Oh, Edwin C.

AU - Topol, Aaron

AU - Shah, Hardik R.

AU - Klei, Lambertus L.

AU - Kramer, Robin

AU - Pinto, Dalila

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AU - Cicek, A. Ercument

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AU - Browne, Andrew

AU - Lu, Cong

AU - Xie, Lu

AU - Readhead, Ben

AU - Stahl, Eli A.

AU - Xiao, Jianqiu

AU - Parvizi, Mahsa

AU - Hamamsy, Tymor

AU - Fullard, John F.

AU - Wang, Ying Chih

AU - Mahajan, Milind C.

AU - Derry, Jonathan M.J.

AU - Dudley, Joel T.

AU - Hemby, Scott E.

AU - Logsdon, Benjamin A.

AU - Talbot, Konrad

AU - Raj, Towfique

AU - Bennett, David A.

AU - De Jager, Philip L.

AU - Zhu, Jun

AU - Zhang, Bin

AU - Sullivan, Patrick F.

AU - Chess, Andrew

AU - Purcell, Shaun M.

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AU - Brennand, Kristen J.

AU - Katsanis, Nicholas

AU - Domenici, Enrico

AU - Devlin, Bernie

AU - Sklar, Pamela

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N2 - 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.

AB - 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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Gene expression elucidates functional impact of polygenic risk for schizophrenia

Abstract

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