Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms
Abstract 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 sub...
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doaj-dbafa41f027b40dd8f5ac8b8259d14352020-12-08T14:11:25ZengNature Publishing GroupTranslational Psychiatry2158-31882020-11-0110111010.1038/s41398-020-01093-wNovel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptomsKlara Mareckova0Colin Hawco1Fernanda C. Dos Santos2Arin Bakht3Navona Calarco4Amy E. Miles5Aristotle N. Voineskos6Etienne Sibille7Ahmad R. Hariri8Yuliya S. Nikolova9Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke UniversityCampbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH)Abstract 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 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.https://doi.org/10.1038/s41398-020-01093-w |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Klara Mareckova Colin Hawco Fernanda C. Dos Santos Arin Bakht Navona Calarco Amy E. Miles Aristotle N. Voineskos Etienne Sibille Ahmad R. Hariri Yuliya S. Nikolova |
spellingShingle |
Klara Mareckova Colin Hawco Fernanda C. Dos Santos Arin Bakht Navona Calarco Amy E. Miles Aristotle N. Voineskos Etienne Sibille Ahmad R. Hariri Yuliya S. Nikolova Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms Translational Psychiatry |
author_facet |
Klara Mareckova Colin Hawco Fernanda C. Dos Santos Arin Bakht Navona Calarco Amy E. Miles Aristotle N. Voineskos Etienne Sibille Ahmad R. Hariri Yuliya S. Nikolova |
author_sort |
Klara Mareckova |
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_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_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_sort |
novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms |
publisher |
Nature Publishing Group |
series |
Translational Psychiatry |
issn |
2158-3188 |
publishDate |
2020-11-01 |
description |
Abstract 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 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. |
url |
https://doi.org/10.1038/s41398-020-01093-w |
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