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Meta-Analysis
. 2018 Jul 1;84(1):18-27.
doi: 10.1016/j.biopsych.2018.01.017. Epub 2018 Feb 19.

Opposite Molecular Signatures of Depression in Men and Women

Marianne L Seney  1 , Zhiguang Huo  2 , Kelly Cahill  2 , Leon French  3 , Rachel Puralewski  4 , Joyce Zhang  4 , Ryan W Logan  5 , George Tseng  6 , David A Lewis  4 , Etienne Sibille  7
Affiliations
Meta-Analysis

Opposite Molecular Signatures of Depression in Men and Women

Marianne L Seney et al. Biol Psychiatry. .

Abstract

Background: Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex.

Methods: To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions: the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (26 men, 24 women with MDD and sex-matched control subjects). Results were further analyzed using a threshold-free approach, Gene Ontology, and cell type-specific analyses. A separate dataset was used for independent validation (13 MDD subjects/sex and 22 control subjects [13 men, 9 women]).

Results: Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, in which the overall transcriptional profile of MDD was opposite in men and women. Gene Ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types.

Conclusions: The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.

Keywords: Corticolimbic; Depression; Genetics; Meta-analysis; Mood disorders; Sex difference.

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Figures

Figure 1
Figure 1. Distinct transcriptional changes in men and women with MDD
(A) Venn diagram displaying overlap in differentially expressed genes in men with MDD, in women with MDD, and in genes identified via meta-regression for sex (q < 0.05). We confirmed these results using an independent replication dataset (p < 0.05); there was very little overlap in DE genes identified in men and women with MDD in BA25 (B) and BA11 (C).
Figure 2
Figure 2. Genes affected in opposite directions in men and women with MDD
(A) Scatterplot indicating the overall pattern of opposite effect size directions for the full meta-regression by sex gene list (1027 genes). (B) Heatmap indicating opposite effect sizes of the 52 genes significantly (q < 0.05) changed in opposite directions in men and women with MDD. These genes were identified in both the meta-regression dataset as well as in the sex-specific meta-analysis datasets.
Figure 3
Figure 3. Verification of meta-regression results using arrays in the ACC
The MD2 ACC microarray experiments were performed at the same time in men and women with MDD, allowing us to directly compare expression changes from the microarray studies. There were significant sex x diagnosis interactions for ARPP21 (A), P2RY12 (B), CACNA1I (C), SLCO1A2 (D), ARHGEF3 (E), GABRD (F), and CAMK2B (G). There was a significant main effect of diagnosis on expression of NOL3 (I), NUB1 (J), and PSMA3 (K). (A) There was a significant increase in ARPP21 expression in only women with MDD. (B) There was a trend for a decrease in P2RY12 expression in only women with MDD. (C) There was a significant decrease in CACNA1I expression in only men with MDD. (D) There was a decrease in SLC01A2 expression in only women with MDD. (E) There was an increase in ARHGEF3 expression in only women with MDD. (F) There was a trend for a decrease in GABRD expression in only men with MDD. (G) There was a decrease in CAMK2B expression in only men with MDD. (H) There was a trend for a decrease in MTHFR expression in only men with MDD. (I) There was a significant decrease in NOL3 expression in both men and women with MDD. (J) There was a significant increase in NUB1 expression in both men and women with MDD. (K) There was a significant decrease in PSMA3 expression in men and women with MDD. *, p < 0.05; **, p < 0.01; #, p < 0.1.
Figure 4
Figure 4. Threshold-free differential expression patterns reveal that men and women with MDD have opposite molecular signatures
(A) Schematic indicating interpretation of RRHO plots. A hot spot in the bottom left corner indicates overlap in genes up in both men and women with MDD. A hot spot in the top right corner indicates overlap in genes down in both men and women with MDD. A hot spot in the top left indicates overlap in genes up in men and down in women with MDD. A hot spot in the bottom right indicates overlap in genes down in men and up in women with MDD. Note that in the RRHO plots, the quadrants are not always of equal size; this is due to the fact that there is typically not an even split in the number of genes that are up and down regulated. (B) There was no significant overlap in genes that were up in both men and women with MDD or down in both men and women with MDD. However, there was a weak overlap in genes that were changed in opposite directions in men and women with MDD. There was a strong overlap in genes that were affected in opposite directions in the DLPFC (C) and ACC (D) of men and women with MDD. (E) There was no overlap in gene expression profiles in the AMY.
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