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Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response
Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 yea...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884410/ https://www.ncbi.nlm.nih.gov/pubmed/33589590 http://dx.doi.org/10.1038/s41398-021-01248-3 |
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author | Marshe, Victoria S. Maciukiewicz, Malgorzata Hauschild, Anne-Christin Islam, Farhana Qin, Li Tiwari, Arun K. Sibille, Etienne Blumberger, Daniel M. Karp, Jordan F. Flint, Alastair J. Turecki, Gustavo Lam, Raymond W. Milev, Roumen V. Frey, Benicio N. Rotzinger, Susan Foster, Jane A. Kennedy, Sidney H. Kennedy, James L. Mulsant, Benoit H. Reynolds, Charles F. Lenze, Eric J. Müller, Daniel J. |
author_facet | Marshe, Victoria S. Maciukiewicz, Malgorzata Hauschild, Anne-Christin Islam, Farhana Qin, Li Tiwari, Arun K. Sibille, Etienne Blumberger, Daniel M. Karp, Jordan F. Flint, Alastair J. Turecki, Gustavo Lam, Raymond W. Milev, Roumen V. Frey, Benicio N. Rotzinger, Susan Foster, Jane A. Kennedy, Sidney H. Kennedy, James L. Mulsant, Benoit H. Reynolds, Charles F. Lenze, Eric J. Müller, Daniel J. |
author_sort | Marshe, Victoria S. |
collection | PubMed |
description | Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10(−6)) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10(−6)), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10(−6), FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer’s disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10(−4)). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction. |
format | Online Article Text |
id | pubmed-7884410 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78844102021-02-25 Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response Marshe, Victoria S. Maciukiewicz, Malgorzata Hauschild, Anne-Christin Islam, Farhana Qin, Li Tiwari, Arun K. Sibille, Etienne Blumberger, Daniel M. Karp, Jordan F. Flint, Alastair J. Turecki, Gustavo Lam, Raymond W. Milev, Roumen V. Frey, Benicio N. Rotzinger, Susan Foster, Jane A. Kennedy, Sidney H. Kennedy, James L. Mulsant, Benoit H. Reynolds, Charles F. Lenze, Eric J. Müller, Daniel J. Transl Psychiatry Article Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10(−6)) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10(−6)), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10(−6), FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer’s disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10(−4)). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction. Nature Publishing Group UK 2021-02-15 /pmc/articles/PMC7884410/ /pubmed/33589590 http://dx.doi.org/10.1038/s41398-021-01248-3 Text en © The Author(s) 2021 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/. |
spellingShingle | Article Marshe, Victoria S. Maciukiewicz, Malgorzata Hauschild, Anne-Christin Islam, Farhana Qin, Li Tiwari, Arun K. Sibille, Etienne Blumberger, Daniel M. Karp, Jordan F. Flint, Alastair J. Turecki, Gustavo Lam, Raymond W. Milev, Roumen V. Frey, Benicio N. Rotzinger, Susan Foster, Jane A. Kennedy, Sidney H. Kennedy, James L. Mulsant, Benoit H. Reynolds, Charles F. Lenze, Eric J. Müller, Daniel J. Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response |
title | Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response |
title_full | Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response |
title_fullStr | Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response |
title_full_unstemmed | Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response |
title_short | Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response |
title_sort | genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884410/ https://www.ncbi.nlm.nih.gov/pubmed/33589590 http://dx.doi.org/10.1038/s41398-021-01248-3 |
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