Major depressive disorder (MDD) is a leading contributor to disease burden worldwide. 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. Systematic resequencing of the CREB1 gene in affected members of these families has identified rare sequence variants at positions −656 and −115 that appear to cosegregate with unipolar mood disorders in two large multigenerational families and three small nuclear families, respectively. Results from previous transfection experiments that employed constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene support the hypothesis that the A−656 allele contributes to the development of MDD in women by selectively increasing the activity of the CREB1 promoter in brain cell lines exposed to 17 β-estradiol. Analogous transfection experiments described in the current study revealed that the G−115 promoter variant reduced promoter activity in CATH.a neuronal cells regardless of the hormonal environment, consistent with the observation that increased risk for unipolar mood disorders conferred by this allele was not limited by sex. The effects of CREB1 promoter variants on promoter activity, their influence on the development of mood disorders and related clinical features, and the interaction of their phenotypic expression with sex seem likely to be complex and allele-specific rather than a general property of the CREB1 locus. © 2010 Wiley-Liss, Inc.