Mapping Genes of Schizophrenia in Selected Dagestan Isolates

Abstract

Key methods for mapping complex disease genes include haplotype analysis of affected and healthy members of pedigrees and linkage analysis using nonparametric and parametric approaches. Dagestan indigenous ethnics, whose villages were in strict marital and geographical isolation over hundreds of generations, are viable candidates for the implementation of this mapping strategy. The population structures led to high genetic differentiation between these isolates and low genetic diversity within them. Our study indicated that haplotype analysis in schizophrenia (SCZ) pedigrees enables visualization of significantly smaller regions in haplotype blocks in patient’s genealogies, compared to linkage analysis. We combined haplotype and linkage analysis to improve our efforts in finding genomic regions with pathogenic loci during mapping genes of this complex disease. The results obtained from these analyses clearly demonstrate locus and/or allele heterogeneity or homogeneity of SCZ between isolates and within pedigrees with common ancestors. Haplotype analysis was performed using the computer package SimWalk2. Based on genotyped patients and healthy relatives, this program reconstructed the probable haplotypes derived from inaccessible direct ancestors. It is therefore possible to evaluate the numbers of meioses and recombination events in generations. Results obtained suggest that risk alleles within the same short tandem repeat (STR) locus in haplotype blocks found to be associated with same clinical phenotype vary between different genetic isolates. Next steps in the analyses related with genome-wide nonparametric and parametric linkage analyses of STRs with SCZ. The genome-wide nonparametric analyses performed in four isolates indicated that primary isolates generally have greater genetic homogeneity in loci linked with SCZ, in comparison with secondary isolates. Our linkage analysis of pedigrees found that 17 chromosomes out of 22 autosomes have linkage signals with schizophrenia in all four genetic isolates we studied. These results show a nearly twofold reduction in the number of linked loci in genomes, i.e., genomic homogeneity of pathogenic loci linked to schizophrenia in demographically older primary isolates (PIs), in comparison with demographically younger genetically heterogeneous secondary isolates (SIs). From 17 total loci linked with SCZ in all four genetic isolates, in each PI we obtained an average of 4.5 linked loci, while in each SI the mean linked number of loci was 9. Historically young SI, which passed fewer meioses and recombination events in their demographic history, also showed larger genomic regions linked to the SCZ, while the PI accumulated more meioses and recombinants in smaller genomic regions. The number of observed recombinations may consequently be higher in PI, but cannot be identified due to the high genetic homogeneity of these types of isolates. PIs have 1.8 times fewer SCZ-linked genomic regions, as well as smaller sizes of linked genomic regions, compared with SI, indicated by the higher genomic heterogeneity of loci linked with SCZ and by the larger size of linked genomic regions. 10 of the 25 genomic regions linked with SCZ are replicated in two or more of the studied isolates, which supports that revealed pathogenic loci are generalizable for SCZ to ethnogenomic stratification of isolates we study, i.e., demonstrate interpopulation genetic homogeneity in the pathogenic loci of schizophrenia. Most reliable across genetic isolates studied with high LOD scores are linkages at 6p22-p23, 10q26, 17p12-q12, and 22q11.23-q12.3. The linkage results with genome-wide scanned markers in isolates with varying degrees of demographic antiquity and aggregation of SCZ suggest narrowing of the genome region linked with the pathogenic locus as the PI; the greater the number of meiosis and recombinations in the history of the isolate, the greater the probability for detecting a physical linkage of pathogenic loci in the studied genomic markers.