A review of the relationship between the <i>SLC6A4</i> gene and mental disorders

The SLC6A4 gene, which encodes the serotonin (5-hydroxytryptamine; 5-HT) transporter, plays an important role in the pathogenesis of mental disorders by regulating serotonin reuptake in the synaptic cleft. This review summarizes current evidence on the associations of SLC6A4 polymorphisms, epigenetic modifications, and neuroimaging findings with schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD), and other psychiatric conditions. Studies have shown that the impact of SLC6A4 polymorphisms varies across ethnic groups and populations. Epigenetic studies indicate that DNA methylation in the promoter and exon regions of SLC6A4 can inhibit gene expression and exacerbate imbalances in the 5-HT signaling pathway, which are closely related to negative symptoms in SCZ, childhood trauma, and gender-specific risks for MDD. Neuroimaging evidence further suggests that SLC6A4 polymorphisms and methylation status are significantly associated with brain structural and functional abnormalities, pointing to a multidimensional mechanism involving ontogeny, epigenetics, and neural networks. Moreover, alterations in SLC6A4 have also been implicated in BD and attention-deficit/hyperactivity disorder. Despite significant progress, challenges remain, including ethnic biases in study populations, discrepancies between epigenetic patterns in peripheral and central nervous systems, and unclear mechanisms underlying gene-environment interactions. Future research should integrate multi-omics approaches, large cross-ethnic cohorts, and gender-stratified analyses to elucidate the precise regulatory network of SLC6A4 in mental disorders.