Effects of the G(-656)A variant on CREB1 promoter activity in a glial cell line: interactions with gonadal steroids and stress.

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the CREB1 region to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G to A transition at position -656 in the CREB1 promoter cosegregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A(-656) allele contributes to the development of MDD in women by selectively altering the activity of the CREB1 promoter in glial cells exposed to 17 beta-estradiol. Furthermore, the exaggeration of this effect during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations. The results of in silico analysis revealed four putative binding sites for transcription factors that are affected by the G to A transition at position -656, of which CP2 best fit the experimental observations.