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.

Figure 1

Genome scan results (MDD-RE). The line represents the value of Z_lr at each point on the multipoint map across the genome, in cM. Vertical bars separate the chromosomes (chromosome numbers are shown at the bottom of the graph area). Significant linkage was observed on chromosome 15q (103.2 cM).

Figure 2

Linkage analysis of chromosome 15 (MDD-RE). The blackened circles and dark black line represent Z_lr scores (left Y-axis) across the multipoint map of chromosome 15 in cM. The lighter line represents ALLEGRO’s information content measure (right Y-axis). Marker names are shown at the bottom of the graph area.