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Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shift...

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Autores principales: Mareckova, Klara, Hawco, Colin, Dos Santos, Fernanda C., Bakht, Arin, Calarco, Navona, Miles, Amy E., Voineskos, Aristotle N., Sibille, Etienne, Hariri, Ahmad R., Nikolova, Yuliya S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686479/
https://www.ncbi.nlm.nih.gov/pubmed/33235204
http://dx.doi.org/10.1038/s41398-020-01093-w
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author Mareckova, Klara
Hawco, Colin
Dos Santos, Fernanda C.
Bakht, Arin
Calarco, Navona
Miles, Amy E.
Voineskos, Aristotle N.
Sibille, Etienne
Hariri, Ahmad R.
Nikolova, Yuliya S.
author_facet Mareckova, Klara
Hawco, Colin
Dos Santos, Fernanda C.
Bakht, Arin
Calarco, Navona
Miles, Amy E.
Voineskos, Aristotle N.
Sibille, Etienne
Hariri, Ahmad R.
Nikolova, Yuliya S.
author_sort Mareckova, Klara
collection PubMed
description Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults (225 men; age 19.79 +/− 1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and increases in neural response to emotional faces and shapes in men (multivariate p < 0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.
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spelling pubmed-76864792020-12-03 Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms Mareckova, Klara Hawco, Colin Dos Santos, Fernanda C. Bakht, Arin Calarco, Navona Miles, Amy E. Voineskos, Aristotle N. Sibille, Etienne Hariri, Ahmad R. Nikolova, Yuliya S. Transl Psychiatry Article Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults (225 men; age 19.79 +/− 1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and increases in neural response to emotional faces and shapes in men (multivariate p < 0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia. Nature Publishing Group UK 2020-11-24 /pmc/articles/PMC7686479/ /pubmed/33235204 http://dx.doi.org/10.1038/s41398-020-01093-w Text en © The Author(s) 2020, corrected publication 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
Mareckova, Klara
Hawco, Colin
Dos Santos, Fernanda C.
Bakht, Arin
Calarco, Navona
Miles, Amy E.
Voineskos, Aristotle N.
Sibille, Etienne
Hariri, Ahmad R.
Nikolova, Yuliya S.
Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
title Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
title_full Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
title_fullStr Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
title_full_unstemmed Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
title_short Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
title_sort novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686479/
https://www.ncbi.nlm.nih.gov/pubmed/33235204
http://dx.doi.org/10.1038/s41398-020-01093-w
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