Malignancy of recurrent, early‐onset major depression: A family study

Abstract

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.

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

“…For females, the D2S2944 124-bp allele was significantly more common in cases than controls (odds ratio 4.5, 95% CI 1.9-10.8). These results were supported by evidence from a within-family transmission disequilibrium test of the D2S2944 124-bp allele in another sample of 81 families previously identified through individuals with recurrent early-onset MDD (Zubenko et al, 2001). This finding argues against population stratification as a trivial explanation of the association by linkage disequilibrium.…”

Risk for recurrence in depression

“…The results of family studies suggest that the familial transmission of recurrent depression is even stronger than the familial transmission of depression in general (Klein, Lewinsohn, Rohde, Seeley, & Durbin, 2002;Zubenko et al, 2001), particularly if it is early-onset recurrent depression (Moldin, Reich, & Rice, 1991). Increased recurrence risk in offspring could reflect environmental contributions stemming from a disorganized home life that includes being reared by a parent who is repeatedly compromised by episodic depression during the child's upbringing.…”

Effects of the G(−656)A variant on CREB1 promoter activity in a neuronal cell line: Interactions with gonadal steroids and stress

“…1 Families identified by individuals with recurrent, early-onset MDD (RE-MDD), a severe and strongly familial form of MDD, have provided an important resource in efforts to identify and characterize genes that contribute to the risk of developing MDD and related conditions. 1,2 Model-free linkage analysis of a region of chromosome 2q33-35, highlighted by previous case-control studies 3,4 and supported by within-family analyses employing the transmission disequilibrium test, 5 has revealed evidence of sex-specific linkage to unipolar mood disorders extending over 15 cM in our 81 RE-MDD families. 6,7 Peak multipoint LOD scores of 6.33 and 6.87 occurred at D2S2321 and D2S2208, respectively.…”

“…[8][9][10] CREB has also been implicated in neuronal plasticity, cognition and longterm memory, 12 abnormalities of which commonly occur in patients with MDD, may predispose patients to the onset or recurrence of MDD and may be related to the eventual development of irreversible dementia in some patients. 1,13 Finally, reports of synergistic interactions of CREB with nuclear estrogen receptors [14][15][16] may provide a mechanism by which CREB facilitates sex-specific patterns of gene expression that manifest themselves in the sex-specific effects of risk alleles for unipolar mood disorders.…”