Human NPY promoter variation rs16147:T>C as a moderator of prefrontal NPY gene expression and negative affect

Studies in humans and animals suggest a role for NPY in the mediation of behavioral stress responses. Here, we examined whether the NPY promoter variant rs16147:T>C is functional for expression of NPY in a brain region relevant for behavioral control, anxiety and depression, the anterior cingulate cortex. In silico analysis of DNA structural profile changes produced by rs16147 variation suggests allelic differences in protein binding at the rs16147 site. This was confirmed by electrophoretic mobility shift assay, demonstrating that the rs16147 C-allele has strongly reduced affinity for a yet unknown factor compared to the T-allele. Analyzing 107 human post-mortem brain samples we show that allelic variation at rs16147 contributes to regulation of NPY mRNA and peptide levels in this region. Specifically, the C-allele leads to increased gene expression. In agreement with the molecular findings, rs16147:T>C is associated with anxiety and depressive symptoms in 314 young adults via a gene x environment interaction with early childhood adversity, replicating the recent finding of rs16147-C as a risk factor for stress related psychopathology. Our results show the importance of rs16147:T>C for regulation of NPY gene expression and brain function.