Sequence variations in CREB1 cosegregate with depressive disorders in women.

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.

D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women.

Recurrent, early-onset, major depressive disorder (RE-MDD) is a strongly familial condition whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. Sixteen of the 19 candidate susceptibility loci identified by a recent genome survey revealed allelic associations with RE-MDD in men or women, but not in both sexes. The association of D2S2944 alleles and genotypes with RE-MDD and related disorders was evaluated using a case-control study design employing 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. The results of the case-control study were subsequently evaluated in a sample of 81 families ascertained through probands with RE-MDD using the transmission/disequilibrium test. The frequency of the D2S2944 124-bp allele among women with RE-MDD was approximately three times that for female controls (P = 0.0003). Women who carried the D2S2944 124-bp allele revealed a significantly elevated risk of developing RE-MDD, as indicated by an odds ratio of 4.5 compared to female controls (P<0.001). In contrast, men with RE-MDD did not have an increased frequency of this allele compared to male controls, and men who were carriers did not exhibit an increased risk of developing RE-MDD or related disorders. Our findings also suggest that the D2S2944 124-bp allele increases the risk of alcohol and other substance use disorders among women with RE-MDD. The transmission/disequilibrium test provided confirmatory evidence of these sex-specific findings within families. The results of this study confirm the existence of sex-specific susceptibility loci for RE-MDD, and suggest that there may be important differences in the molecular pathophysiology of RE-MDD in men and women. Alternatively, our findings may reflect the existence of sex-specific differences in the molecular mechanisms that determine resilience to endogenous or environmental depressogenic stimuli. The identification and characterization of the D2S2944 susceptibility locus for RE-MDD and related substance use disorders is likely to provide important new insights into the clinical biology, treatment, and prevention of these disorders.

Malignancy of recurrent, early-onset major depression: a family study.

Coordinated efforts to identify susceptibility genes for unipolar major depressive disorder (MDD) and related disorders are now underway. These studies have focused on recurrent, early-onset MDD (RE-MDD), the most heritable form of this disorder. The goal of this study was to characterize the burden of MDD and other mood disorders, comorbid mental disorders, and excess mortality in RE-MDD families. A total of 81 families were identified through probands over the age of 18, who met criteria for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic, unipolar MDD (RE-MDD), and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Approximately half of the first-degree relatives and a quarter of extended relatives of RE-MDD probands suffered from at least one mood disorder, typically MDD. As commonly observed for other oligogenic, multifactorial disorders, the severity of MDD reflected by age at onset and number of episodes attenuated with increasing familial/genetic distance from the proband. A substantial fraction of RE-MDD probands and their first-degree relatives met diagnostic criteria for additional psychiatric disorders that include prominent disturbances of mood. The deceased relatives of RE-MDD probands died at a median age that was 8 years earlier than for the local population; over 40% died before reaching age 65. These differences in mortality statistics resulted from a shift toward younger ages at death across the lifespan, including a fivefold increase in the proportion of individuals who died in the first year of life. Several-fold increases in the proportion of deaths by suicide, homicide, and liver disease were observed among the relatives of RE-MDD probands. However, the rank order of the three most common causes of death-heart disease, cancer, and stroke-remained unchanged and differences in the proportions of deaths from the remaining causes were small. RE-MDD is a strongly familial condition with a high rate of psychiatric comorbidity, whose malignant effects have a significant negative impact on the health and longevity of patients and their family members.