Major depressive disorder (MDD) is a complex psychiatric illness, with synaptic plasticity playing a key role in its pathology. Our study aims to investigate the molecular basis of MDD by analyzing synaptic plasticity-related gene expression at the single-cell level. Utilizing a published snRNA-seq dataset (GSE144136), we identified Excitatory.neurons_1 as the cell cluster most associated with MDD and synaptic plasticity through cell clustering, gene set enrichment analysis (GSEA), and pseudotime analysis. Integrating the bulk RNA-seq data (GSE38206), we identified CASKIN1 and CSTB as hub genes via differential expression analysis and machine learning methods. Further exploration of the relevant mechanisms was performed via cell–cell communication and ligand-receptor interaction analysis, functional enrichment analysis, and the construction of molecular regulatory networks, highlighting miR-21-5p as a key biomarker. We propose that elevated miR-21-5p in MDD downregulates CASKIN1 in Excitatory.neurons_1 cells, resulting in decreased neural connectivity and altered synaptic plasticity. As our analyzed snRNA-seq dataset consists solely of male samples, these findings may be male-specific. Our findings shed light on potential mechanisms underlying synaptic plasticity in MDD, offering novel insights into the disorder’s cellular and molecular dynamics.

Background/Objectives: Short tandem repeat (STR) loci are widely used in forensic genetics for identification and kinship analysis. Traditionally, these loci were selected to avoid medical associations, but recent studies suggest that loci such as TH01 and D16S539 may be linked to psychiatric conditions like schizophrenia. This study explores these potential associations and considers the privacy implications related to disease susceptibility. Methods: We analyzed 19 STR loci, including CODIS core loci and additional loci like Penta D and Penta E. Statistical analyses were conducted on a dataset of schizophrenia patients and matched control individuals to assess the relationship between STR polymorphisms and schizophrenia risk. Results: No significant associations were found between the 19 analyzed loci and schizophrenia in this dataset. While initial analyses revealed minor allele frequency differences at the D3S1358, D13S317, and TPOX loci between the schizophrenia and control groups, these differences did not retain statistical significance following Bonferroni correction (corrected p < 0.0026 for all loci). Conclusions: Although no significant associations were found between STR loci and schizophrenia, this study highlights the importance of considering the potential for forensic DNA data to reveal health-related information. As forensic DNA databases continue to expand, there is a growing need to reassess ethical and legal guidelines to ensure the protection of individual privacy. Future research should continue exploring these genetic associations with larger, more diverse samples to further understand their implications.

Schizophrenia is a severe psychiatric disorder with a complex etiology. Emerging evidence implicates the gut microbiota in its pathogenesis via the microbiota-gut-brain axis, although causal relationships remain unclear. We used a two-sample Mendelian randomization (MR) approach to investigate potential causal links between gut microbial taxa and schizophrenia. To provide a biological context for these findings, we performed 16S rRNA V3-V4 sequencing of fecal samples from an independent cohort of individuals with schizophrenia (SCZ, n = 21) and matched healthy controls (HC, n = 21). Forward MR analysis revealed a significant causal association between seven microbial taxa and schizophrenia risk. Notably, a higher genetically predicted abundance of Bifidobacterium was associated with increased schizophrenia risk (OR = 1.47, 95 %CI: 1.05–2.05), with results robust to multivariable adjustment. Reverse MR found no evidence of reverse causation. In the independent cohort, exploratory 16S rRNA analysis of the top 15 most abundant genera revealed nominal differences, including Bifidobacterium, Megamonas, Streptococcus, and Fusicatenibacter, but none remained significant after FDR correction (all Q > 0.05). However, a targeted confirmatory analysis of four MR-identified taxa revealed significant group differences for three taxa (all Q = 0.010), whereas Lachnospiraceae did not. By integrating MR with 16S rRNA V3-V4 sequencing, this study provides convergent evidence for a potential causal role of specific gut microbial taxa, particularly Bifidobacterium, in contributing to schizophrenia risk. Our findings underscore the context-dependent nature of host-microbiota interactions and support the need for strain-level and functional studies to further elucidate schizophrenia pathogenesis.