Sequence variations in CREB1 cosegregate with depressive disorders in women

Abstract

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous linkage studies have identified a 451 kb region of 2q33-35 that exhibited significant evidence of linkage to Mood Disorders among women (but not men) from families with recurrent, early-onset MDD (RE-MDD), a severe and strongly familial subtype of MDD. This 451 kb region includes CREB1, an attractive susceptibility gene for MDD and related disorders. Sequence variations in the CREB1 promoter and intron 8 have been detected that cosegregate with Mood Disorders, or their absence, in women from these families, identifying CREB1 as a sex-limited susceptibility gene for unipolar Mood Disorders. These findings implicate the cAMP signaling pathway in the pathophysiology of Mood Disorders and related conditions. Molecular Psychiatry (2003) 8, 611-618. doi:10.1038/sj.mp.4001354Keywords: genetics; CREB1; depression; sex-specific; women Major depressive disorder (MDD) is characterized by two or more weeks of depressed mood or impaired enjoyment, accompanied by disturbances of sleep and appetite, psychomotor changes, impaired concentration, inappropriate guilt, and suicidal thoughts or actions. 1 Most epidemiologic and family studies indicate that the lifetime prevalence of MDD is between 5 and 10%, with women twice as likely to be affected as men. 1-3 Suicide, a tragic consequence of MDD, has been reported to occur in 10-15% of patients who were previously hospitalized for depression, 4 a rate of death that is three orders of magnitude greater than that reported for the American population as a whole. 5 In addition to suicide, an even greater absolute increase in age-specific mortality from natural causes has been reported for individuals who suffer from MDD and their family members. 6 The significance of these public health problems has been highlighted by two recent reports from the Surgeon General. 3,5 In a study conducted by the World Health Organization, MDD ranked second only to ischemic heart disease as a source of disability worldwide. 7 Twin studies have demonstrated that genetic factors typically account for 40-70% of the risk for developing MDD, and adoption studies have confirmed the important role played by genetic risk factors in the development of MDD (for reviews, see US Department of Health and Human Services 3 ; Zubenko et al 6 ). Early age at onset of the first major depressive episode, as well as recurrence, are independent factors that increase the morbid risk of MDD among family members. In a recent study of 81 extended families (407 first-degree relatives and 835 extended relatives) ascertained through adult probands with recurrent (X2 episodes), early-onset (onset p25 years) MDD (RE-MDD), 6 over one-third of first-degree relatives and nearly one-fifth of extended relatives suffered from MDD, prevalence rates that were 7.7 and 3.8 times greater than the corresponding population rates reported by the Epidemiologic Catchment Area Study. 2 The results of a genetic se...

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

“…Other possible candidate genes include GPR55 (G protein-coupled receptor 55), which is expressed in human brain tissue and involved in extracellularintracellular signal transduction, and HDAC4 (histone deacetylase 4) which participates in epigenetic modification of core histones and. Work by Zubenko and colleagues has also suggested a role of CREB1 on mood disorders; this lies 20 cM centromeric to our linkage peak (Zubenko et al, 2003a). These authors have also identified a sex-specific association between the 124bp repeat allele of D2S944 and recurrent, early-onset major depression and with anxious depression in an independent U.S. and Dutch sample (Beem et al, 2006;Philibert et al, 2003;Zubenko et al, 2002).…”

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

“…A female-specific association between BPAD and/or SCZ has been previously observed in both GPR50 15 and CREB1. 36 However, we cannot definitively say that there is no effect in males because the 95% CIs of the ORs in the male groups overlap with those of the ORs in the female samples where the significance was observed, indicating that there is no significant difference between their respective ORs. Alternatively, it is possible that the association detected in the females is a false-positive.…”

“…Thus, we deemed it necessary to test the hypotheses that GPR78 may be involved in the pathogenesis of BPAD, SCZ or both BPAD and SCZ, in which all affected individuals were grouped together, as it has been previously suggested that the two psychiatric illnesses may share susceptibility loci. 33,34 Similarly, owing to evidence of differences between males and females in the manifestation of psychiatric illness 35 and from findings of sex-specific association in the analysis of other candidate genes, 15,36 analysis was also carried out on samples separated on the basis of gender.…”

Major leads in the search for susceptibility genes for depression

“…The studies of Zubenko et al 3,11 are the first specific molecular genetic studies of early-onset and recurrent depression to be reported. The two studies of Zubenko et al upon which this commentary will focus are the most recent of a series of studies arising from this group's focus on early-onset recurrent illness.…”

“…14 A model-free sex-dependent linkage analysis 15 of 2q33-35 (which contains D2S29944) reported that the highest multipoint LOD scores (between 6 and 7) were found in female affected relative pairs at D2S2321 and D2S2208, in a region containing CREB1-the gene for the cAMP-responsive element-binding protein (CREB). A subsequent linkage analysis of sequence variations in the CREB1 promoter and intron 8 11 reported that variants at these regions cosegregated with mood disorders in females in two of the 31 families that gave positive lod scores for this gene.…”