Sex-stratified genome-wide association meta-analysis of major depressive disorder, 2025, Thomas et al

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Sex-stratified genome-wide association meta-analysis of major depressive disorder

Jodi T. Thomas, Jackson G. Thorp, Floris Huider, Poppy Z. Grimes, Rujia Wang, Pierre Youssef, Jonathan R. I. Coleman, Enda M. Byrne, Mark Adams, BIONIC consortium, The GLAD Study, Sarah E. Medland, Ian B. Hickie, Catherine M. Olsen, David C. Whiteman, Heather C. Whalley, Brenda W.J.H. Penninx, Hanna M. van Loo, Eske M. Derks, Thalia C. Eley, Gerome Breen, Dorret I. Boomsma, Naomi R. Wray, Nicholas G. Martin & Brittany L. Mitchell

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Abstract
There are striking sex differences in the prevalence and symptomology of Major Depressive Disorder.

Here, we conduct the largest sex-stratified genome wide association and genotype-by-sex interaction meta-analyses of Major Depressive Disorder to date (Females: 130,471 cases, 159,521 controls. Males: 64,805 cases, 132,185 controls). We identify 16 and eight independent genome-wide significant variants in females and males, respectively, including one novel variant on the X chromosome.

Major Depressive Disorder in females and males shows substantial genetic overlap with a large proportion of variants displaying similar effect sizes across sexes. However, we also provide evidence for a higher burden of genetic risk in females which could be due to female-specific variants.

Additionally, sex-specific pleiotropic effects may contribute to the higher prevalence of metabolic symptoms in females with Major Depressive Disorder.

These findings underscore the importance of considering sex-specific genetic architectures in the study of health conditions, including Major Depressive Disorder, paving the way for more targeted treatment strategies.

Web | PDF | Nature Communications | Open Access

 

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NEGR1 and DCC were the only two genes that were significant in both males and females (using different tests).

Despite these similarities, we found very little overlap in genes associated with MDD between sexes. Both our gene-based tests and the annotation of genome-wide significant SNPs identified only one gene significantly associated with MDD in females and males; DCC (gene-based test) and NEGR1 (SNP annotation). Both genes are involved in neuronal connectivity and genetic variants in these and related genes have previously been associated with psychiatric disorders including MDD39,40,41.

NEGR1 and DCC also happen to be the genes closest to the 10th and 15th most significant loci in the DecodeME study (though below the genome-wide significance threshold at 1.19e-7 and 2.47e-7 respectively).

I think this is unlikely to be a coincidence. I suppose there is a possibility that they are significant in DecodeME only because a third of the cases also have depression. Either way, I think DecodeME and the above study provide further evidence that these genes are actually important in some way for some disease, whether depression, ME/CFS, or both.

Some other interesting findings from this study:

Gene-set analysis using gene-level statistics for all genes revealed that in females, SNPs were significantly enriched for two biological processes; central nervous system neuron development (pBonferroni = 0.036) and central nervous system neuron differentiation (pBonferroni = 0.045). No significant gene sets were found in males. As many gene-set databases emphasise developmental genes, the female enrichments may partly reflect this bias.

To explore further, we conducted a gene-property analysis using BrainSpan gene expression data across 11 brain developmental stages. SNPs from both sexes were significantly enriched for expression in the ‘late mid-prenatal’ stage, with additional ‘early mid-prenatal’ enrichment in females (Supplementary Fig. 14). These findings support the involvement of neurodevelopmental processes indicated by gene-set analysis.

Gene-property analysis for tissue specificity using 30 general tissue types (GTEx v8) identified SNPs from both the female and male stratified GWAS analyses as significantly enriched for gene expression in brain tissue, while pituitary tissue was significantly enriched only in the female SNPs (Supplementary Fig. 15A).

Furthermore, using 53 tissues types (GTEx v8), both sexes showed significant enrichment for gene expression in the cortex and frontal cortex, caudate, putamen and nucleus accumbens basal ganglia, hippocampus, amygdala, hypothalamus and anterior cingulate cortex. Only female SNPs were significantly enriched for gene expression in the cerebellum and cerebellar hemisphere (Supplementary Fig. 15B). The differing results likely reflect the power imbalance between our female and male GWAS meta-analyses.