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Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics
Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide assoc...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785/ https://www.ncbi.nlm.nih.gov/pubmed/34035472 http://dx.doi.org/10.1038/s41386-021-01023-4 |
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author | Lam, Max Chen, Chia-Yen Ge, Tian Xia, Yan Hill, David W. Trampush, Joey W. Yu, Jin Knowles, Emma Davies, Gail Stahl, Eli A. Huckins, Laura Liewald, David C. Djurovic, Srdjan Melle, Ingrid Christoforou, Andrea Reinvang, Ivar DeRosse, Pamela Lundervold, Astri J. Steen, Vidar M. Espeseth, Thomas Räikkönen, Katri Widen, Elisabeth Palotie, Aarno Eriksson, Johan G. Giegling, Ina Konte, Bettina Hartmann, Annette M. Roussos, Panos Giakoumaki, Stella Burdick, Katherine E. Payton, Antony Ollier, William Chiba-Falek, Ornit Koltai, Deborah C. Need, Anna C. Cirulli, Elizabeth T. Voineskos, Aristotle N. Stefanis, Nikos C. Avramopoulos, Dimitrios Hatzimanolis, Alex Smyrnis, Nikolaos Bilder, Robert M. Freimer, Nelson B. Cannon, Tyrone D. London, Edythe Poldrack, Russell A. Sabb, Fred W. Congdon, Eliza Conley, Emily Drabant Scult, Matthew A. Dickinson, Dwight Straub, Richard E. Donohoe, Gary Morris, Derek Corvin, Aiden Gill, Michael Hariri, Ahmad R. Weinberger, Daniel R. Pendleton, Neil Bitsios, Panos Rujescu, Dan Lahti, Jari Le Hellard, Stephanie Keller, Matthew C. Andreassen, Ole A. Deary, Ian J. Glahn, David C. Huang, Hailiang Liu, Chunyu Malhotra, Anil K. Lencz, Todd |
author_facet | Lam, Max Chen, Chia-Yen Ge, Tian Xia, Yan Hill, David W. Trampush, Joey W. Yu, Jin Knowles, Emma Davies, Gail Stahl, Eli A. Huckins, Laura Liewald, David C. Djurovic, Srdjan Melle, Ingrid Christoforou, Andrea Reinvang, Ivar DeRosse, Pamela Lundervold, Astri J. Steen, Vidar M. Espeseth, Thomas Räikkönen, Katri Widen, Elisabeth Palotie, Aarno Eriksson, Johan G. Giegling, Ina Konte, Bettina Hartmann, Annette M. Roussos, Panos Giakoumaki, Stella Burdick, Katherine E. Payton, Antony Ollier, William Chiba-Falek, Ornit Koltai, Deborah C. Need, Anna C. Cirulli, Elizabeth T. Voineskos, Aristotle N. Stefanis, Nikos C. Avramopoulos, Dimitrios Hatzimanolis, Alex Smyrnis, Nikolaos Bilder, Robert M. Freimer, Nelson B. Cannon, Tyrone D. London, Edythe Poldrack, Russell A. Sabb, Fred W. Congdon, Eliza Conley, Emily Drabant Scult, Matthew A. Dickinson, Dwight Straub, Richard E. Donohoe, Gary Morris, Derek Corvin, Aiden Gill, Michael Hariri, Ahmad R. Weinberger, Daniel R. Pendleton, Neil Bitsios, Panos Rujescu, Dan Lahti, Jari Le Hellard, Stephanie Keller, Matthew C. Andreassen, Ole A. Deary, Ian J. Glahn, David C. Huang, Hailiang Liu, Chunyu Malhotra, Anil K. Lencz, Todd |
author_sort | Lam, Max |
collection | PubMed |
description | Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing. |
format | Online Article Text |
id | pubmed-8357785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-83577852021-08-30 Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics Lam, Max Chen, Chia-Yen Ge, Tian Xia, Yan Hill, David W. Trampush, Joey W. Yu, Jin Knowles, Emma Davies, Gail Stahl, Eli A. Huckins, Laura Liewald, David C. Djurovic, Srdjan Melle, Ingrid Christoforou, Andrea Reinvang, Ivar DeRosse, Pamela Lundervold, Astri J. Steen, Vidar M. Espeseth, Thomas Räikkönen, Katri Widen, Elisabeth Palotie, Aarno Eriksson, Johan G. Giegling, Ina Konte, Bettina Hartmann, Annette M. Roussos, Panos Giakoumaki, Stella Burdick, Katherine E. Payton, Antony Ollier, William Chiba-Falek, Ornit Koltai, Deborah C. Need, Anna C. Cirulli, Elizabeth T. Voineskos, Aristotle N. Stefanis, Nikos C. Avramopoulos, Dimitrios Hatzimanolis, Alex Smyrnis, Nikolaos Bilder, Robert M. Freimer, Nelson B. Cannon, Tyrone D. London, Edythe Poldrack, Russell A. Sabb, Fred W. Congdon, Eliza Conley, Emily Drabant Scult, Matthew A. Dickinson, Dwight Straub, Richard E. Donohoe, Gary Morris, Derek Corvin, Aiden Gill, Michael Hariri, Ahmad R. Weinberger, Daniel R. Pendleton, Neil Bitsios, Panos Rujescu, Dan Lahti, Jari Le Hellard, Stephanie Keller, Matthew C. Andreassen, Ole A. Deary, Ian J. Glahn, David C. Huang, Hailiang Liu, Chunyu Malhotra, Anil K. Lencz, Todd Neuropsychopharmacology Article Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing. Springer International Publishing 2021-05-25 2021-09 /pmc/articles/PMC8357785/ /pubmed/34035472 http://dx.doi.org/10.1038/s41386-021-01023-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lam, Max Chen, Chia-Yen Ge, Tian Xia, Yan Hill, David W. Trampush, Joey W. Yu, Jin Knowles, Emma Davies, Gail Stahl, Eli A. Huckins, Laura Liewald, David C. Djurovic, Srdjan Melle, Ingrid Christoforou, Andrea Reinvang, Ivar DeRosse, Pamela Lundervold, Astri J. Steen, Vidar M. Espeseth, Thomas Räikkönen, Katri Widen, Elisabeth Palotie, Aarno Eriksson, Johan G. Giegling, Ina Konte, Bettina Hartmann, Annette M. Roussos, Panos Giakoumaki, Stella Burdick, Katherine E. Payton, Antony Ollier, William Chiba-Falek, Ornit Koltai, Deborah C. Need, Anna C. Cirulli, Elizabeth T. Voineskos, Aristotle N. Stefanis, Nikos C. Avramopoulos, Dimitrios Hatzimanolis, Alex Smyrnis, Nikolaos Bilder, Robert M. Freimer, Nelson B. Cannon, Tyrone D. London, Edythe Poldrack, Russell A. Sabb, Fred W. Congdon, Eliza Conley, Emily Drabant Scult, Matthew A. Dickinson, Dwight Straub, Richard E. Donohoe, Gary Morris, Derek Corvin, Aiden Gill, Michael Hariri, Ahmad R. Weinberger, Daniel R. Pendleton, Neil Bitsios, Panos Rujescu, Dan Lahti, Jari Le Hellard, Stephanie Keller, Matthew C. Andreassen, Ole A. Deary, Ian J. Glahn, David C. Huang, Hailiang Liu, Chunyu Malhotra, Anil K. Lencz, Todd Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics |
title | Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics |
title_full | Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics |
title_fullStr | Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics |
title_full_unstemmed | Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics |
title_short | Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics |
title_sort | identifying nootropic drug targets via large-scale cognitive gwas and transcriptomics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785/ https://www.ncbi.nlm.nih.gov/pubmed/34035472 http://dx.doi.org/10.1038/s41386-021-01023-4 |
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