Differential and spatial expression meta-analysis of genes identified in genome-wide association studies of depression

Abstract

Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and affects individuals of all ages. It causes significant psychosocial impairments and is a major cause of disability. A recent consortium study identified 102 genetic variants and 269 genes associated with depression. To provide targets for future depression research, we prioritized these recently identified genes using expression data. We examined the differential expression of these genes in three studies that profiled gene expression of MDD cases and controls across multiple brain regions. In addition, we integrated anatomical expression information to determine which brain regions and transcriptomic cell types highly express the candidate genes. We highlight 12 of the 269 genes with the most consistent differential expression: MANEA, UBE2M, CKB, ITPR3, SPRY2, SAMD5, TMEM106B, ZC3H7B, LST1, ASXL3, ZNF184 and HSPA1A. The majority of these top genes were found to have sex-specific differential expression. We place greater emphasis on ZNF184 as it is the top gene in a more conservative analysis of the 269. Specifically, the differential expression of ZNF184 was strongest in subcortical regions in males and females. Anatomically, our results suggest the importance of the dorsal lateral geniculate nucleus, cholinergic, monoaminergic and enteric neurons. These findings provide a guide for targeted experiments to advance our understanding of the genetic underpinnings of depression.

A Sex-Specific Genome-Wide Association Study of Depression Phenotypes in UK Biobank

“…Here we directly explored sex-dependency in the genetic architecture of MDD, by performing a follow-up analysis of a published GWAS for 'broad depression' (31) after stratifying the analysis by sex. Our findings are consistent with previous twin studies revealing sex-specific genetic architecture to clinical depression, and implicate sex-specific molecular pathways, aligned with genome-wide transcriptomic analyses (32).…”

Transcriptome-wide and stratified genomic structural equation modeling identify neurobiological pathways shared across diverse cognitive traits

“…Major depressive disorder 30 , anxiety disorders 31 , schizophrenia 32 , and bipolar disorder 33 have all been associated with lower cognitive function. In addition, major depressive disorder 34 and schizophrenia 35 have been associated with two of the top g hits from the current analyses: ZNF184 and PRSS16 , respectively. As a natural extension of these convergent findings, we find that top gene expression hits on g explained a significant proportion of the genetic overlap across g and these psychiatric traits.…”

“…Both g and the top gene expression hits for g have been associated with several clinically relevant outcomes. This includes previously described associations for Alzheimer’s disease and ZSCAN9 42 , for major depressive disorder (MDD) 34 and Parkinson’s disease (PD) 43 and ZNF184 , and for schizophrenia (SCZ) 35 and PRSS16 . Following up on this work, we examined whether these patterns of gene expression explained a significant proportion of the genetic overlap across g and these correlates of g by utilizing publicly available GWAS summary statistics for ALZ 44 PD 45 , MDD 46 , and SCZ 19 .…”

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

“…6 ). Moreover, 58 differentially regulated transcripts identified in this study overlapped candidates from three gene expression studies of MDD [ 45 , 109 ] (Supplementary Tables T S24 ), a vast majority of which were altered in multiple regions beyond the single region profiled in the respective human studies (e.g. Arhgef25 , Kmt2a , Mettl9 , Rhoa , Mgat4c) .…”