Genetics of recurrent early-onset major depression (GenRED): final genome scan report.

OBJECTIVE: The authors carried out a genomewide linkage scan to identify chromosomal regions likely to contain genes that contribute to susceptibility to recurrent early-onset major depressive disorder, the form of the disorder with the greatest reported risk to relatives of index cases. METHOD: Microsatellite DNA markers were studied in 656 families with two or more such cases (onset before age 31 in probands and age 41 in other relatives), including 1,494 informative "all possible" affected relative pairs (there were 894 independent affected sibling pairs). Analyses included a primary multipoint allele-sharing analysis (with ALLEGRO) and a secondary logistic regression analysis taking the sex of each relative pair into account (male-male, male-female, female-female). RESULTS: Genomewide suggestive evidence for linkage was observed on chromosome 15q25-q26 (at 105.4 centimorgans [cM]). The authors previously reported genomewide significant linkage in this region in the first 297 families. In the secondary analysis, after empirical genomewide correction for multiple testing, suggestive linkage results were observed on chromosome 17p12 (28.0 cM, excess sharing in male-male and male-female pairs) and on chromosome 8p22-p21.3 (25.1 cM, excess sharing in male-male pairs). CONCLUSIONS: These regions of chromosomes 15q, 17p, and 8p might contain genes that contribute to susceptibility to major depression and related disorders. Evidence for linkage has been reported independently in the same regions of chromosome 15q for major depression and of chromosome 8p for related personality traits.

Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

Genetics of recurrent early-onset depression (GenRED): design and preliminary clinical characteristics of a repository sample for genetic linkage studies.

This is an initial report on a six-site collaborative project, Genetics of Recurrent Early-Onset Depression (GenRED). This is a study of a large sample of families with recurrent major depressive disorder (DSM-IV) beginning by the age 30 in probands or 40 in relatives. Evidence suggests that early onset and recurrence of depressive episodes predict substantially increased risk of depression in first-degree relatives compared with the general population, suggesting that susceptibility genes might be mapped with this phenotype. The projected sample of 800-1,000 affected sibling pairs (ASPs) and other relatives will be studied using genome scan methods. Biological materials and blinded clinical data will be made available through the NIMH cell repository program. The sample should have good-to-excellent power to detect a locus associated with a 24% or greater population-wide increase in risk to siblings. We describe 838 affected individuals from the first 305 families containing 434 independent ASPs, or 613 ASPs counting all possible pairs. The mean age at the onset was 18.5 years, with a mean of 7.3 episodes and longest episode of 655 days. Almost all subjects had experienced at least 4 weeks of depression with five or more additional symptom criteria. Frequencies of symptoms and psychiatric and medical comorbid are provided. Substance use was more common in males, and panic disorder in females. Within pairs of affected siblings, correlations were significant for age at onset, substance abuse/dependence, panic disorder, obsessive-compulsive disorder and nicotine initiation and persistence. We replicated previously reported associations among comorbid panic disorder and social phobia, chronicity of depression and suicidal behavior. This suggests comparability of our cases to those in earlier large family studies. This dataset should prove useful for genetic studies of a highly familial form of major depressive disorder.