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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2016
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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. |
format | Online Article Text |
id | pubmed-5083142 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
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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