Genomewide Significant Linkage to Recurrent, Early-Onset Major Depressive Disorder on Chromosome 15q

Abstract

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.

Enhanced linkage of a locus on chromosome 2 to premature coronary artery disease in the absence of hypercholesterolemia

“…1 In 1000 simulations under the null hypothesis of no linkage, at least one LOD score peak X4.4 was reached 40 times, giving a genome-wide significance of 0.04. (In fact, in each of these 40 simulations only one such peak was observed if, following Holmans et al, 12 two peaks are considered to define two different linkage regions when they were separated by 30 cM or more. )…”

“…The use of covariates in linkage analysis has contributed to mapping or confirming the position of genes for prostate cancer, 8,9 late-onset Alzheimer disease 10,11 and recurrent early-onset depression. 12 In this study, we report the results of a sibling pair linkage analysis of CAD on chromosome 2 using the British Heart Foundation (BHF) Family Heart Study including hypercholesterolemia as a covariate.…”

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…In addition, there is evidence that autosomal genes contribute to sex differences in the genetic predisposition to psychiatric phenotypes. For example, chromosomal loci implicated in the vulnerability to major depression (Holmans et al, 2004;Nash et al, 2004), neuroticism (Fullerton et al, 2003), obsessive-compulsive disorder (OCD; Nestadt et al, 2000), and autism (Stone et al, 2004) differ between men and women. Such differences occur against a background of a sex difference in heritability estimates for some disorders; eg the heritability of major depression is greater in women than in men (Kendler et al, 2006).…”

A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

“…50 Our finding of a BP susceptibility locus on chromosome 15q25-26 is supported by evidence of linkage with other mood and psychotic disorders. In a study of major depressive disorder (MDD), Holmans et al 51 reported a significant multipoint LOD score of 3.73 between the markers D15S652 and D15S816 (90.3-92.8 Mb) in a genome-wide scan. The authors discuss the unclear relationship between major depressive disorder and BP, with BPII being especially difficult to differentiate from major depressive disorder.…”