Study links schizophrenia to age-related changes in a stress-response gene

The researchers examined existing data from postmortem human brain samples. They included 378 people with major psychiatric disorders and 209 control participants across two independent cohorts. The psychiatric group included people who had lived with schizophrenia, major depressive disorder, or bipolar disorder.

The team focused on two areas of the frontal cortex: the dorsolateral prefrontal cortex and the orbitofrontal cortex. These are parts of the brain’s outer layer. They studied DNA methylation, gene activity, genetic information, and features of individual brain cells.

DNA methylation is a chemical tag attached to DNA. It does not change the underlying genetic code. Instead, it can affect how easily a gene is used by a cell. The researchers looked closely at FKBP5, the gene that makes a protein called FKBP51. This protein is involved in regulating glucocorticoid receptor signaling, part of the system through which the body responds to stress hormones.

The study identified several methylation sites near a regulatory region of FKBP5 called a proximal enhancer. An enhancer is a stretch of DNA that can help control how active a nearby gene is. At these sites, lower DNA methylation was associated with greater FKBP5 gene expression. The researchers found this relationship in both cohorts.

Single-nucleus analyses, which examine information from individual cell nuclei rather than only a blended tissue sample, supported the relevance of these associations across the major cell types studied. That does not mean every cell changed in the same way, but it suggests the finding was not limited to just one broad cell category.

Among participants with schizophrenia, the researchers found significantly lower DNA methylation in the FKBP5 enhancer region. The differences were especially noted at sites associated with glucocorticoid response elements, pieces of DNA involved in responding to stress-hormone signaling. Age and a genetic variant called rs1360780 were also associated with methylation patterns in this region.

The journal abstract supports a link between aging, psychiatric diagnosis, and changes in FKBP5 methylation in the frontal cortex. It suggests these epigenetic changes may help explain related differences in FKBP5 messenger RNA, the molecular instruction used to make a protein. The news coverage describes this as a stress gene that may switch on more easily, but the study itself reports associations in donated tissue rather than directly testing stress responses in living people.

That distinction matters. The study cannot establish whether lower methylation came before schizophrenia, developed during the illness, was related to aging, or reflected other factors not detailed in the supplied abstract. It also cannot show that the changes damage brain circuits or raise a person’s future chance of developing a psychiatric condition.

No medicine or other intervention was tested. FKBP5 has been discussed as a possible target for psychiatric treatments, but this research does not show that changing FKBP5 would be safe or effective for schizophrenia or any other condition. Further work would need to confirm the findings, examine the timing of these changes, and test whether they can be safely influenced in people.