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

Wu, Wennie; Howard, Derek; Sibille, Etienne; French, Leon

doi:10.1038/s41398-020-01127-3

Cited by 24 publications

(19 citation statements)

References 85 publications

(109 reference statements)

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“…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).…”

Section: Introductionsupporting

confidence: 92%

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

Silveira

Pokhvisneva

Howard

et al. 2022

Preprint

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Background There are marked sex differences in the prevalence, phenotypic presentation and treatment response for major depression. While genome-wide association studies (GWAS) adjust for sex differences, to date no studies seek to identify sex-specific markers and pathways. In this study we performed a sex-stratified genome-wide association analysis for broad depression. Methods A genome-wide association study for broad depression was performed in the UK Biobank total participants (N=274,141), including only non-related participants, as well as separately in males (N=127,867) and females (N=146,274). Bioinformatics analyses were performed to characterize common and sex-specific markers and associated processes/pathways. Results We identified 11 loci passing genome level significance (P < 5 × 10−8) in females and one in males. In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies, however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in males. Gene-based analysis revealed Regulation of Gene Expression as a common biological process, but suggested sex-specific molecular mechanisms. Finally, sex-specific PRSs for broad depression outperformed total and the opposite sex PRSs in the prediction of broad MDD. Conclusions These findings provide evidence for sex-dependent genetic pathways for clinical depression as well as for health conditions comorbid with depression.

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Section: Introductionsupporting

confidence: 92%

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

Silveira

Pokhvisneva

Howard

et al. 2022

Preprint

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“…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) .…”

Section: Discussionmentioning

confidence: 87%

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

et al. 2022

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Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI. We performed multimodal analysis of SSRI response in 27 mammalian brain regions using 310 bulk RNA-seq and H3K27ac ChIP-seq datasets, followed by in-depth characterisation of two hippocampal regions using single-cell RNA-seq (20 datasets). Remarkably, fluoxetine induced profound region-specific shifts in gene expression and chromatin state, including in the nucleus accumbens shell, locus coeruleus and septal areas, as well as in more well-studied regions such as the raphe and hippocampal dentate gyrus. Expression changes were strongly enriched at GWAS loci for depression and antidepressant drug response, stressing the relevance to human phenotypes. We observed differential expression at dozens of signalling receptors and pathways, many of which are previously unknown. Single-cell analysis revealed stark differences in fluoxetine response between the dorsal and ventral hippocampal dentate gyri, particularly in oligodendrocytes, mossy cells and inhibitory neurons. Across diverse brain regions, integrative omics analysis consistently suggested increased energy metabolism via oxidative phosphorylation and mitochondrial changes, which we corroborated in vitro; this may thus constitute a shared mechanism of action of fluoxetine. Similarly, we observed pervasive chromatin remodelling signatures across the brain. Our study reveals unexpected regional and cell type-specific heterogeneity in SSRI action, highlights under-studied brain regions that may play a major role in antidepressant response, and provides a rich resource of candidate cell types, genes, gene regulatory elements and pathways for mechanistic analysis and identifying new therapeutic targets for depression and anxiety.

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“…Major depressive disorder (MDD) is a major mental disorder with high mortality and disability [ 1 , 2 ]. The most common pathophysiological explanation of MDD relies on the monoamine hypothesis, which indicates that depressive symptoms relate to a lack of neurotransmitters such as serotonin [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

MANF/EWSR1/ANXA6 pathway might as the bridge between hypolipidemia and major depressive disorder

Zheng

Zhao

et al. 2022

Transl Psychiatry

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Major depressive disorder (MDD) involves changes in lipid metabolism, but previous findings are contradictory. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is considered to be a regulator of lipid metabolism. To date, the function of MANF has been studied in many brain disorders, but not in MDD. Therefore, to better understand the role of lipids in MDD, this study was conducted to examine lipid levels in the serum of MDD patients and to investigate the potential function of MANF in MDD. First, the data on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) in serum from 354 MDD patients and 360 healthy controls (HCs) were collected and analyzed. The results showed that there were significantly lower concentrations of TC and LDL-C in MDD patients compared with HCs, and TC levels were positively correlated with LDL-C levels. Bioinformatics analysis indicated that MANF/EWSR1/ANXA6 pathway might serve as the connecting bridge through which hypolipidemia played a functional role in MDD. Second, to verify this hypothesis, serum samples were collected from 143 MDD patients, and 67 HCs to measure the levels of MANF, EWSR1, and ANXA6 using ELISA kits. The results showed that compared to HCs, MDD patients had a significantly lower level of MANF and higher levels of ANXA6 and EWSR1, and these molecules were significantly correlated with both TC level and Hamilton Depression Rating Scales (HDRS) score. In addition, a discriminative model consisting of MANF, EWSR1, and ANXA6 was identified. This model was capable of distinguishing MDD subjects from HCs, yielded an area under curve of 0.9994 in the training set and 0.9569 in the testing set. Taken together, our results suggested that MANF/EWSR1/ANXA6 pathway might act as the bridge between hypolipidemia and MDD, and these molecules held promise as potential biomarkers for MDD.

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

Cited by 24 publications

References 85 publications

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

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

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

MANF/EWSR1/ANXA6 pathway might as the bridge between hypolipidemia and major depressive disorder

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