Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

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 schizophrenia cases (N = 258) and control subjects (N = 279), creating a resource of gene expression an...

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Autores principales: 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, Ben, Stahl, Eli A, Parvizi, Mahsa, Hamamsy, Tymor, Fullard, John F, Wang, Ying-Chih, Mahajan, Milind C, Derry, Jonathan M J, Dudley, Joel, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083142/
https://www.ncbi.nlm.nih.gov/pubmed/27668389
http://dx.doi.org/10.1038/nn.4399
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author 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, Ben
Stahl, Eli A
Parvizi, Mahsa
Hamamsy, Tymor
Fullard, John F
Wang, Ying-Chih
Mahajan, Milind C
Derry, Jonathan M J
Dudley, Joel
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
author_facet 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, Ben
Stahl, Eli A
Parvizi, Mahsa
Hamamsy, Tymor
Fullard, John F
Wang, Ying-Chih
Mahajan, Milind C
Derry, Jonathan M J
Dudley, Joel
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
author_sort Fromer, Menachem
collection PubMed
description 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 schizophrenia cases (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 changes neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yields abnormal migration. Of 693 genes showing significant case/control differential expression, their fold changes are ≤ 1.33, and an independent cohort yields similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.
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spelling pubmed-50831422017-03-26 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, Ben Stahl, Eli A Parvizi, Mahsa Hamamsy, Tymor Fullard, John F Wang, Ying-Chih Mahajan, Milind C Derry, Jonathan M J Dudley, Joel 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 Nat Neurosci Article 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 schizophrenia cases (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 changes neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yields abnormal migration. Of 693 genes showing significant case/control differential expression, their fold changes are ≤ 1.33, and an independent cohort yields similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases. 2016-09-26 2016-11 /pmc/articles/PMC5083142/ /pubmed/27668389 http://dx.doi.org/10.1038/nn.4399 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
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, Ben
Stahl, Eli A
Parvizi, Mahsa
Hamamsy, Tymor
Fullard, John F
Wang, Ying-Chih
Mahajan, Milind C
Derry, Jonathan M J
Dudley, Joel
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
title Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
title_full Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
title_fullStr Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
title_full_unstemmed Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
title_short Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia
title_sort gene expression elucidates functional impact of polygenic risk for schizophrenia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083142/
https://www.ncbi.nlm.nih.gov/pubmed/27668389
http://dx.doi.org/10.1038/nn.4399
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