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

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 (N=424) of older adults in relation to ante-mortem depressive symptoms. Additionally, we integrated genome-wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 14,048 unique genes in seven cell types and 52 cell subtypes to perform a transcriptome-wide association study (TWAS) of depression followed by Mendelian randomization. Results Our single-nucleus TWAS analysis identified 68 candidate genes for depression, which showed the greatest number being in excitatory and inhibitory neurons. 53 of 68 genes were novel compared to previous studies. Notably, gene expression in different neuronal subtypes have varying effects on depression risk. Higher genetically correlated traits with depression, such as neuroticism, shared more TWAS genes than less correlated traits. Complementing these analyses, differential gene expression analysis across 52 neocortical cell subtypes showed that genes such as KCNN2, SCAI, WASF3 and SOCS6 are associated with late-life depressive symptoms in specific cell subtypes. Conclusions These two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depressive symptoms and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.