Genetic Variation Shapes MECP2-Dependent Vulnerability to Stress-Related Adverse Mental Health Trajectories in Women

The multi-factorial origin of stress vulnerability remains incompletely understood, hampering the implementation of targeted prevention. As interplays between genes and environment lie at the basis of individual variability, epigenetic mechanisms are considered important mediators of adverse mental health trajectories following stressful experiences. We have previously demonstrated that the X-linked epigenetic factor Methyl-CpG binding protein 2 (MECP2) plays a role in stress susceptibility, with dysfunctional variants in transgenic mice and its downregulation in human populations being associated with a lower ability to cope with adverse events. By leveraging a study of the Italian Twin Registry on mental health during the COVID-19 pandemic, the present study explored whether a genetic component that accounts for individual variability in MECP2 expression may shape risk of developing stress-related mental health deterioration. We report an association between homozygosity for the minor allele of the rs2734647, a single nucleotide polymorphism (SNP) in the MECP2 3’-untranslated region (UTR) that has been linked to allele-specific MECP2 downregulation, and increased symptoms of COVID-19 pandemic-related depression, anxiety and distress in women. Our findings provide additional evidence to the emerging role of MECP2 in stress vulnerability, unveiling the contribution of genetic variation within the MECP2 locus to adverse mental health outcomes in women.