Sex-dependent DNA hypermethylation of SLC6A4 in patients with schizophrenia

Abstract

Schizophrenia (SCZ) is a mental health condition with a complex pathogenic mechanism. One important hypothesis of SCZ pathology is serotonin (5-HT) impairment, and the 5-HT transporter, encoded by the SLC6A4 gene, plays a key role in regulating 5-HT levels. Some studies have confirmed that the CpG island upstream of exon 1 and the island shore region of SLC6A4 are hypermethylated in SCZ; however, to the best of our knowledge, there has been no study on the methylation level of CpG islands downstream of SLC6A4 exon 1. Methylation of CpG islands downstream of SLC6A4 exon 1 was measured in the peripheral blood of SCZ patients with positive symptoms using the MethylTarget method. Overall, the methylation level of SLC6A4 was significantly higher in women than in men. In intergroup comparisons, the level of SLC6A4 methylation was higher in the SCZ group than in the control group, especially within the male subgroup. Moreover, methylation levels of several CpG sites correlated significantly with SCZ. These results suggest that epigenetic alterations of SLC6A4 are related to SCZ pathophysiology. These findings improve the current understanding of the role of the 5-HT system in the pathological development of SCZ.