A large genome-wide association study identified sex-specific genetic differences in major depressive disorder, including a novel X-chromosome variant in males and higher heritability among females.
The investigators analyzed genetic data from 130,471 female and 64,805 male patients with major depressive disorder (MDD) and more than 290,000 controls. Sixteen genome-wide significant variants were identified in females and eight in males. A male-specific variant, rs5971319, was located on the X chromosome near IL1RAPL1, a gene involved in neuronal development.
Heritability estimates indicated a stronger genetic contribution to depression in females. Analyses of polygenicity showed a broader genetic basis for MDD in women. Genetic correlations were stronger between female MDD and body mass index (BMI), metabolic syndrome, attention-deficit/hyperactivity disorder, and smoking than in males. Shared genetic regions across both sexes included NEGR1, while female-specific regions related to BMI involved genes such as DYNC1I2, HTT, and DENND1A.
Most genetic variants influencing depression in males were found to overlap with those influencing females, suggesting a largely shared genetic foundation with sex-dependent effects.
Investigators conducted sex-stratified genome-wide meta-analyses using international data sets. Linkage disequilibrium score regression estimated heritability, MiXeR modeled polygenicity and overlap, and gwas-pw identified shared or sex-specific causal regions.
The study’s limitations included an unequal sample size, which may have increased power to detect female-specific signals. Assumptions regarding lifetime prevalence and unscreened controls may also have influenced heritability estimates. Replication in a smaller independent cohort did not achieve statistical concordance, likely due to limited power.
The investigators concluded that biological sex plays a key role in shaping depression’s genetic architecture. Broader polygenicity and higher heritability in females may reflect the impact of female-specific variants and metabolic pathways, while the male X-linked finding highlights additional mechanisms that warrant study.
Dr. Brittany L. Mitchell, PhD, of the Queensland Institute of Medical Research Berghofer Medical Research Institute in Brisbane, Australia, noted, “These insights into sex-specific genetic mechanisms not only deepen our understanding of the aetiology of MDD but may also inform the development of novel therapeutics that are tailored to sex-specific genetic risk profiles, ultimately contributing to more targeted and effective precision medicine strategies for MDD.”
The investigators reported no competing interests or conflicts of interest.
Source: Nature Communications