TY - JOUR
T1 - A Single-Nucleus Transcriptome-Wide Association Study Implicates Novel Genes in Depression Pathogenesis
AU - Zeng, Lu
AU - Fujita, Masashi
AU - Gao, Zongmei
AU - White, Charles C.
AU - Green, Gilad S.
AU - Habib, Naomi
AU - Menon, Vilas
AU - Bennett, David A.
AU - Boyle, Patricia
AU - Klein, Hans Ulrich
AU - De Jager, Philip L.
N1 - Publisher Copyright:
© 2023 Society of Biological Psychiatry
PY - 2024/7/1
Y1 - 2024/7/1
N2 - Background: Depression, a common psychiatric illness and global public health problem, remains poorly understood across different life stages, which hampers the development of novel treatments. Methods: To identify new candidate genes for therapeutic development, we performed differential gene expression analysis of single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of older adults (n = 424) in relation to antemortem depressive symptoms. Additionally, we integrated genome-wide association study results for depression (n = 500,199) along with genetic tools for inferring the expression of 14,048 unique genes in 7 cell types and 52 cell subtypes to perform a transcriptome-wide association study of depression followed by Mendelian randomization. Results: Our single-nucleus transcriptome-wide association study analysis identified 68 candidate genes for depression and showed the greatest number being in excitatory and inhibitory neurons. Of the 68 genes, 53 were novel compared to previous studies. Notably, gene expression in different neuronal subtypes had varying effects on depression risk. Traits with high genetic correlations with depression, such as neuroticism, shared more transcriptome-wide association study genes than traits that were not highly correlated with depression. Complementing these analyses, differential gene expression analysis across 52 neocortical cell subtypes showed that genes such as KCNN2, SCAI, WASF3, and SOCS6 were associated with late-life depressive symptoms in specific cell subtypes. Conclusions: These 2 sets of analyses illustrate the utility of large single-nucleus RNA sequencing data both to uncover genes whose expression is altered in specific cell subtypes in the context of depressive symptoms and to enhance the interpretation of well-powered genome-wide association studies so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.
AB - Background: Depression, a common psychiatric illness and global public health problem, remains poorly understood across different life stages, which hampers the development of novel treatments. Methods: To identify new candidate genes for therapeutic development, we performed differential gene expression analysis of single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of older adults (n = 424) in relation to antemortem depressive symptoms. Additionally, we integrated genome-wide association study results for depression (n = 500,199) along with genetic tools for inferring the expression of 14,048 unique genes in 7 cell types and 52 cell subtypes to perform a transcriptome-wide association study of depression followed by Mendelian randomization. Results: Our single-nucleus transcriptome-wide association study analysis identified 68 candidate genes for depression and showed the greatest number being in excitatory and inhibitory neurons. Of the 68 genes, 53 were novel compared to previous studies. Notably, gene expression in different neuronal subtypes had varying effects on depression risk. Traits with high genetic correlations with depression, such as neuroticism, shared more transcriptome-wide association study genes than traits that were not highly correlated with depression. Complementing these analyses, differential gene expression analysis across 52 neocortical cell subtypes showed that genes such as KCNN2, SCAI, WASF3, and SOCS6 were associated with late-life depressive symptoms in specific cell subtypes. Conclusions: These 2 sets of analyses illustrate the utility of large single-nucleus RNA sequencing data both to uncover genes whose expression is altered in specific cell subtypes in the context of depressive symptoms and to enhance the interpretation of well-powered genome-wide association studies so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.
KW - Depressive symptoms
KW - Genome-wide association study
KW - Major depressive disorder
KW - ROSMAP
KW - Single-nucleus RNA-seq
KW - Transcriptome-wide association study
UR - http://www.scopus.com/inward/record.url?scp=85185591196&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2023.12.012
DO - 10.1016/j.biopsych.2023.12.012
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C2 - 38141910
AN - SCOPUS:85185591196
SN - 0006-3223
VL - 96
SP - 34
EP - 43
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 1
ER -