In a recent study, published in Nature Molecular Psychiatry, researchers have performed a sex-stratified genome-wide association analysis for MDD on data from the UK Biobank. Results show that there is evidence for sex-dependent genetic pathways for clinical depression, as well as for health conditions co-morbid with depression.
The gender mental-health gap
Major depressive disorder (MDD) is a common mental health condition that requires prompt and effective treatment to improve quality of life. It is the leading contributor to the global burden of disease and disability worldwide.
Evidence suggests MDD may affect more women than men, with women experiencing more frequent and severe symptoms and related health issues. The way depression affects the brain also differs between men and women, with distinct changes in brain structure, cell-type composition and sex-specific transcriptional signatures in corticolimbic brain regions associated with mood disorders. This may explain why men and women often respond differently to antidepressant treatments.
While genetics play a role in depression, previous genome-wide association studies (GWASs) that combine data from both sexes have likely missed important differences between males and females. While the evidence suggests sex-specific approaches to treatment are potentially the best way forward, until now the precision medicine approach in the area of MDD has advanced without a comprehensive understanding of sex-specific genetic pathways. Understanding these differences could help develop more precise treatments.
Different sexes, different networks
The UK Biobank is a group of over 500,000 people from all over the UK who agreed to share information about their genes and health between 2006-2010. After implementing certain exclusion criteria and only selecting those with the “broad depression” phenotype, this left 113,769 cases and 208,811 controls for the study. The researchers then performed sex-specific GWASs on males and females separately.
The study found that there are significant genetic correlations between depression and a range of other diseases, particularly cardio-metabolic conditions, and that these correlations are different in males and females. There were stronger and more pervasive genetic correlations in females than males, particularly with measures of academic achievement, and the most striking sex difference was between broad MDD and GWASs for metabolic features (such as body fat, waist circumference, etc.) which were significant only in females. The study also performed genetic correlations between their own sex-specific MDD GWASs and previously published sex-specific GWASs for ADHD and for fasting insulin. They found that male and female specific MDD GWASs significantly correlated with ADHD GWASs but not with fasting insulin GWASs.
A gene-based enrichment analysis of the GWASs identified 147 genes significantly associated with broad depression, with 64 genes in females and 53 in males. Twenty-four genes were common to both sexes, with enrichment in biological processes related to sensory perception and G protein-coupled receptor signaling pathways. The most significant common pathway was glutathione metabolism, which is involved in antioxidant defence and regulation of gene expression.
“Regulation of gene expression” was the most significant GO (Gene Ontology) process associated with genes from both male and female MDD GWASs. However, while this process was commonly enriched in both sexes, they were due to sex-specific gene network differences(Figure 1). In males, “regulation of gene expression” was mapped to TCF4, a known regulator of DNA methylation, as well as a large number of genes coding for histone protein variants. However, in females, “regulation of gene expression” was associated with a number of neurexin-related genes – neurexins are presynaptic cell adhesion proteins that are involved in connecting neurons at the synapse.
Several other diseases were associated with genes from both males and females, but again this was due to different sex-specific gene networks (Figure 1). In males, disease was associated with genes involved in epigenetic processes and regulation of neurotransmitter release. In females, brain pathology was related to dopamine receptor signalling, as well as the adaptive immune system.
Explaining different treatment outcomes
The study also looked at expression quantitative trait loci (eQTLs), transcription factors, and drug targets, as well as polygenic risk scores. They again found that not only were there distinct differences in males and females, notably that males had a significantly higher percentage of SNP/eQTLs compared to females, and that females had significantly higher eQTLs in specific regions of the brain. They also found that transcription factors associated with genes linked to oxidative stress, apoptosis, and type II diabetes were found in females, whilst genes associated with tissue and neuron differentiation as well as epigenetic processes were found in males.
One interesting finding was how antidepressant treatments appeared to target different biological processes in males and females, which could explain why there are differences in treatment outcomes between sexes. In males, antidepressants appeared to target epigenetic processes (e.g., chromatin assembly), cell cycle regulation, and inflammation. In females, antidepressants appeared to target neuronal migration, regulation of neurotrophic factors and synaptic plasticity, and dopamine neurotransmission.
This study highlights the importance of taking into account sex-specific genetic pathways in MDD both to better understand the disease, as well as improve treatments. The significant differences between males and females brought to light by this study could pave the way for more precise, sex-specific treatments for depression, which may lead to improved outcomes for patients.
