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.

Fig. 1. Overview of this study.

The 269 genes implicated with depression (top) are characterized by several transcriptomic studies (middle). Highlighted are the different brain regions sampled within each study (middle) that will help prioritize the genes (bottom). Other transcriptomic resources that were used (middle) will identify anatomical targets associated with the disease (bottom). Images are from the cited publications, Dr. David M Howard, and Wikimedia Commons (Gray’s Anatomy by Henry Vandyke Carter).

Fig. 2. Heatmap visualizations of differential expression results.

a Study-specific direction signed log(p-values) for the top 12 genes separated by sex and region. Cell colours range from blue to red, which represents lower and higher expression in cases compared to controls, respectively. Colour intensity represents the degree of differential expression. Missing values are marked in gray. b Corrected meta p-values for the same genes across the 8 across-study meta-analyses. Cell colours range from low (yellow) to high (purple) corrected p-values in each meta-analysis. ACC anterior cingulate cortex (two studies), DLPFC dorsal lateral prefrontal cortex, nAcc nucleus accumbens, Ins anterior insula, Sub subiculum, AMY amygdala, SI sex interaction.

Fig. 3. Expression heatmap for the top differentially expressed genes across the 39 mouse cell-type taxa.

Cell colours range from blue to red, which represent depleted and specific expression, respectively. LST1 is not shown because it lacks a homologous mouse gene in the Homologene database.