[Mapping genes related to early onset major depressive disorder in Dagestan genetic isolates]

The purpose of this study was to determine the molecular epidemiology of early onset major depressive disorder (MDD) in genetic isolates of the Caucasus Dagestan indigenous ethnic populations using molecular and statistical population-genetic approaches.

Two multigenerational pedigrees from two diverse remote highland isolates with aggregation of early onset MDD were ascertained within our long-term research program titled 'Dagestan Genetic Heritage, DGH'. The first isolate included 48 cases of MDD (19 living) with 11 suicides committed, and the second included 60 MDD cases (30 living) with 12 suicides committed. The phenotypes of the affected family members were determined using a database containing diagnoses from a regional psychiatric hospital and through our own clinical examinations, which were based on a Russian translation of DIGS software based on the DSM-IV criteria . A 10 cM genomic scan (Weber/CHLC 9.0 STRs) of the 64 affected and non-affected members of the pedigrees was performed and the data was used for multipoint parametric linkage analyses. Following this scan, selected cases were analyzed by Affymetrix 6.0 SNP arrays in order to refine the contribution of copy number variations (CNVs) to the genetic basis of MDD.

We found a total of 18 genomic regions with nominal (LOD>1.3) linkage to MDD across the two isolates. Three genomic regions had genome-wide significant (LOD>3) linkages and were found at 2p13.2-p11.2, 14q31.12-q32.13 and 22q12.3. We also confirmed previous findings for MDD at 4q25, 11p15, 12q23-24, 13q31-32, 18q21-22 and 22q11-13. Six linkage regions were observed in both genetic isolates, while 12 other linkages demonstrated population-specific heterogeneity. We detected CNV rearrangements within 12 of the 18 linkage regions. Affected subjects had the highest rate of genomic instability within the linkage regions at 2p13.2-p11.2, 4q25-q28.2, 7p14.1, 8p23, 14q31.12-q32.13, 18q22.1 and 20p13.

The results obtained in this study suggest that mapping genes of complex diseases, including MDD, across genetically homogeneous isolates can help detect linkage signals and expedite the search for susceptibility genes when combined with methods that detect structural genomic variation in linkage regions.