Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early‐onset, major depression

Abstract

This report describes the results of a model-free linkage analysis of six polymorphic markers, located in a 15 cM region of chromosome 2q33-35, and unipolar Mood Disorders in 81 families identified by probands with Recurrent, Early-Onset Major Depressive Disorder (RE-MDD), a severe and familial form of clinical depression. Our findings reveal significant evidence of linkage of unipolar Mood Disorders to a 451 Kb region of 2q33-34 flanked by D2S2321 and D2S2208 in these families. Increasing peak LOD scores were observed in both the single point and multipoint analyses for Mood Disorder phenotypes whose definitions embodied progressively less stringent severity criteria for inclusion in the affected group. The sex-dependent multipoint linkage analysis of any Major or Minor Mood Disorders produced LOD scores that reached 6.331 and 6.866 at D2S2321 and D2S2208, respectively. Linkage of Mood Disorders to this region was observed exclusively among female affected relative pairs; no suggestion of linkage was observed when male affected relative pairs were analyzed. These observations imply that a sex-specific susceptibility gene in this region contributes to the vulnerability of women in these families to the development of unipolar Mood Disorders that ranged in severity from minor to severe at the time of clinical assessment. The region between the markers that yielded the peak LOD score includes the CREB1 gene, which encodes a cAMP-responsive element-binding protein (CREB) that is a member of the bZIP family of transcription factors. Based on considerable clinical and preclinical evidence, CREB1 is an attractive candidate for a susceptibility gene for unipolar Mood Disorders. The sex-specificity of the susceptibility locus identified by our study may result from reported synergistic interactions of CREB with nuclear estrogen receptors.

Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

“…Interestingly, another female-specific association has recently been reported in the literature and this identified a variant of the CREB gene which displayed significant evidence for linkage to familial recurrent early-onset major depression in female but not in male subjects. 47,48 Zubenko et al 48 reported an LOD score of 8.19 in a region containing the CREB1 gene, which encodes a cAMP responsive element-binding protein (CREB). The CREB protein is thought to interact with oestrogen receptors to promote the transcription of genes containing oestrogen responsive elements, even in the absence of CREB-binding sites.…”

Discovering Endophenotypes for Major Depression

“…The CREB gene has been implicated in the regulation of REM sleep (Graves et al, 2003), memory consolidation, and major depression (Zubenko et al, 2002). The effect of the muscarinic cholinergic 2 receptor gene that has been implicated in MDD in women (Comings et al, 2002) may conceivably be mediated by REM sleep disturbances.…”

“…Fortunately, in certain families, there is preliminary evidence that recurrent, early-onset major depression is linked to a region containing the CREB1 gene. This gene constitutes an attractive candidate as a susceptibility allele for major depression because CREB1 plays major roles in neuronal plasticity, cognition, and memory (Zubenko et al, 2002).…”

Combined Linkage and Association Analyses of the 124-bp Allele of Marker D2S2944 with Anxiety, Depression, Neuroticism and Major Depression

“…Table I summarizes some of the results, emphasizing recurrent early-onset MDD or MDD and the region containing D2S2944 (Camp and Cannon-Albright, 2005, provide another summary and discussion of these and other findings). Zubenko et al (2002a) reported results of a linkage analysis in the region from D2S1384 (200 cM) to D2S434 (215 cM), which included D2S2944 (210 cM). Evidence for linkage did not reach significance (p<0.05) for recurrent early-onset MDD in females, although significant linkage was established for less severe forms of the illness, which were more prevalent in females.…”

“…The results in their study were obtained with a model that included one or both of two covariates: sex of affected pairs and a dichotomized variable which encoded whether or not a family LOD score at D2S2208 was >0 in Zubenko et al (2002a). The latter covariate substantially increased the LOD score.…”