Interaction of FKBP5 variant rs3800373 and city living alters the neural stress response in the anterior cingulate cortex

Psychosocial stress effects of urban living are associated with substantially increased risk for schizophrenia, mood and anxiety disorders, by altering stress-induced activity in the amygdala and pregenual anterior cingulate cortex (ACC). Genetic factors are likely to modulate the impact of city living on stress processing. Growing evidence suggests a key role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of stress-related disorders. Here we investigated the interaction of city living and genetic variation in FKBP5 (rs3800373) on neural activity in stress-sensitive brain systems. Functional magnetic resonance imaging was performed in 31 healthy young adults using the Montreal Imaging Stress Task. Subjects were divided into groups depending on the number of inhabitants of their current residency. There was a significant main effect of city living on neural activity in the amygdala-hippocampus complex, replicating prior findings. Moreover, we found an interaction between rs3800373 and city living modulating responses in the bilateral subgenual ACC and right pregenual ACC. Specifically, only city dwellers carrying the FKBP5 minor risk allele showed increased stress responses in the subgenual and pregenual ACC when compared to those living in small towns. A significant gene-environment interaction on neural stress responses in the amygdala or hippocampus was only found in FKBP5 major allele carriers. These results point to a potential role of the FKBP5 rs3800373 minor risk allele in predisposing those who live in bigger cities to changes of functional responsivity in the pre- and subgenual ACC, thereby increasing the risk for developing stress-related mental disorders.

Automated summary

The psychosocial stress effects of urban living are associated with increased risk for schizophrenia, mood and anxiety disorders due to alterations in stress-induced activity in the amygdala and pregenual anterior cingulate cortex. Genetic factors, such as FKBP5, may modulate the impact of city living on stress processing. The interaction between city living and genetic variation in FKBP5 (rs3800373) was found to modulate responses in the subgenual and pregenual ACC, potentially increasing the risk for developing stress-related mental disorders in city dwellers carrying the FKBP5 minor risk allele.