A Single-Nucleus Transcriptome-Wide Association Study Implicates Novel Genes in Depression Pathogenesis

Lu Zeng; Masashi Fujita; Zongmei Gao; Charles C White; Gilad S Green; Naomi Habib; Vilas Menon; David A Bennett; Patricia Boyle; Hans-Ulrich Klein; Philip L De Jager

doi:10.1016/j.biopsych.2023.12.012

A Single-Nucleus Transcriptome-Wide Association Study Implicates Novel Genes in Depression Pathogenesis

Biol Psychiatry. 2023 Dec 21:S0006-3223(23)01787-0. doi: 10.1016/j.biopsych.2023.12.012. Online ahead of print.

Authors

Affiliations

¹ Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, New York.
² Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
³ Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, Illinois; Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
⁴ Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, Illinois.
⁵ Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, New York. Electronic address: pld2115@cumc.columbia.edu.

PMID: 38141910
DOI: 10.1016/j.biopsych.2023.12.012

Abstract

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.

Keywords: Depressive symptoms; Genome-wide association study; Major depressive disorder; ROSMAP; Single-nucleus RNA-seq; Transcriptome-wide association study.

Abstract

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