[Mapping genes of major recurrent depression in genetic isolates].

We conducted a genome-wide linkage scan in two extended pedigrees ascertained from two Dagestan genetic isolates (N(o)6007 and 6008) with high aggregation of early onset major depressive disorders (MDD). The first pedigree included in total 22 cases of MDD (15 available) and 11 suicides; the second pedigree contained 29 MDD cases (23 available) and 12 suicides. Five linked regions in our study are consistent with previous findings in association and/or linkage studies with MDD: 11p15, 12q23-24, 13q11-32, 18q22 and 22q11-13. We found two novel for early onset MDD genomic regions with significant linkages in N(o)6007 with Lods = 3.1-3.4 at 2p13.2-p11.2 (and some weak signal in the same region for N(o)6008) and at 14q31.12-q32.13. We also obtained suggestive level linkages at 9q33.3-q34.2 (N(o)6008), 13q31.1-q31.2 (N(o)6007), 11p15 (N(o)6008), 17q25.3 (N(o)6007) and 19q13.31-q13.33 (N(o)6008). Six linked regions (1p36.1-p35.2, 2p13.2-p11.2,13q31, 17q25.3, 18q22 and 22q12.3) were consistent across the two isolates' pedigrees while all other linkage regions (5q14.1-q14.3, 9q33.3-q34.2, 13q31.1-q32.1, 14q31.12-q32.13, 20p13) demonstrated population-specific genetic heterogeneity of MDD. Our results suggest that genetic mapping of complex diseases, including MDD, across genetically homogeneous isolates can enrich the harvest of linkage signals and expedite the search for susceptibility genes.

[STR polymorphism in populations of indigenous Daghestan ethnic groups]. / STR-polimorfizm v populiatsiiakh korennykh narodov Dagestana.

Genomic diversity of 21 STR loci has been studied in six ethnic populations of Daghestan (the Caucasus), namely, Avars, Dargins, Kubachians, Lezgins, and Nogais, and the results have been compared with these data for European, African, and East Asian ethnic groups. Daghestan is unique in its ethnic diversity, which is the greatest in the Caucasus: 26 out of approximately 50 autochthonous ethnic groups of the Caucasus live there. The genetic origin of this wide ethnic diversity of Daghestan and the Caucasus as a whole is still obscure. The genetic heterogeneity of Daghestan populations has been found to be lower than that of most other populations in the world. This is explained by a prolonged isolation and gene drift in their demographic history. Generalized genetic distances between ethnic groups calculated for the whole set of loci studied allow differentiating Asian populations from African ones, with European populations occupying intermediate positions. All Daghestan ethnic populations form a distinct common group together with some European populations (Finnish, Polish, and French). Nogais are genetically close to Southeast Asian populations. The genetic closeness and the apparently equal genetic diversity of Daghestan and European populations suggest that the ethnic differentiation of the ancestral populations of Daghestan and European ethnic groups occurred in the earliest populations of modern humans.

[Genetic and epidemiological studies in Dagestan highland isolates]. / Genetiko-épidemiologicheskie issledovaniia v gornykh izoliatakh Dagestana.

Interpopulation differences in the epidemiology and age of onset of complex diseases, as well as expression of some vital parameters, have been found. The relationship between these interpopulation differences and the genetic processes that have been occurring in the populations throughout their history has been demonstrated. The Daghestan genetic isolates studied are characterized by aggregation of certain complex diseases. In each genetic isolate, almost all affected subjects with homogeneous clinical phenotypes belong to the same large pedigree with a limited number of founders. There is evidence for a large variance of the population risk of schizophrenia (morbid risk) in Daghestan isolates (this parameter varies from 0 to 5%). Examination of 211 cases of schizophrenia earlier diagnosed in Daghestan psychiatric hospitals has shown that only 139 of them meet the DSM-IV criteria for schizophrenia. The remaining 72 subjects have, according to DSM-IV criteria, various schizoaffective and affective disorders; all of these subjects are close relatives of the schizophrenic patients. The age of onset of schizophrenia in the isolates studied varies from 14 to 40 years (20.84 +/- 0.568 years). Offspring of consanguineous marriages exhibit later age at onset and a higher risk of schizophrenia than offspring of exogamous marriages. The results of multivariate genetic analysis indicate that different gene complexes are involved in the pathogeneses of early-onset and late-onset forms of schizophrenia. An association of schizophrenia incidence, its age dependence, and reproductive parameters with polymorphisms of some microsatellite loci have been demonstrated.

[Genetic subdivision of Dagestan ethnic populations]. / Geneticheskaia podrazdelennost' étnicheskikh populiatsii Dagestana.

Relationships between ethnic and genetic differentiation with respect to 54 microsatellites have been analyzed in five Daghestan ethnic groups. To detect the microsatellites, human chromosomes 3, 17, and 18 were screened with a step of 10 cM (Weber/CHLC 9.0 markers) at the Mammalian Genotyping Service (National Institute of Health, United States). Comparison of the polymorphism of these loci in Daghestan populations with average worldwide data has revealed generally low heterozygosity in Daghestan populations, which is accounted for by traditional endogamous and consanguineous marriages throughout the history of these populations. The inbreeding coefficient in Daghestan ethnic groups varies from 0.005 to 0.0134 and is close to the worldwide maximum known to date. For some DNA loci, significant differences between the offsprings of consanguineous and exogamous marriages with respect to allele sizes and their variance have been found. The Daghestan ethnic populations studied differ from one another in both the frequencies of common alleles and the presence of rare alleles that are unique for each ethnic group of Daghestan and have not been found in any other population in the world.

[Mapping genes of complex diseases in genetic isolates of Dagestan]. / Kartirovanie genov kompleksnykh zabolevanii v geneticheskikh izoliatakh Dagestana.

Original results of the analysis of genetic linkage between some genomic markers and two complex clinical phenotypes, schizophrenia and mental retardation, in pedigrees from Dagestan genetic isolates are described. Interpopulation differences in the epidemiology of the complex phenotypes were studied and in their genetic linkage was demonstrated. These differences are evidently related to the genetic structure of the isolates determined by their genetic history. The MR epidemiological index characterizing the lifetime morbid risk of schizophrenia varies in the Dagestan isolates studied from 0 to 4.95%, which is almost five times higher than the average worldwide population rate, 1%. Comparative genetic mapping permitted determination of the most probable genetic linkages and associations of loci from chromosomal regions 17p11.1-12, 3q13.3, and a locus from 22q with schizophrenia and locus 12q23 with mental retardation. There is evidence that this approach is effective for detailed study of the relationship between the genetic (allele and locus) and clinical heterogeneity of complex diseases, which favors successful identification of the genes determining them. The study of linkage disequilibrium (LD) in genetic isolates of Daghestan populations (which have a common genetic background) may be an effective methodological approach for revealing the numerous contradictory results of mapping of the same genes of complex disease performed by different researchers in different regions of the world.

[Comparative study of genetic adaptation of the Caucasian highlanders to historic and to the new urban environments]. / Sravnitel'noe izuchenie geneticheskoi adaptatsii gortsev Kavkaza k istoricheskoi i k novoi gorodskoi srede.

Marriage structure and female reproductive characteristics in a highland isolate and an urban population from Dagestan were compared. The studied urban population could be divided into three groups according to ethnic, genetic, and demographic parameters. In the native, highland population, a steady selection occurred due to a high, uncontrolled birthrate and a high prereproductive mortality. The genetic structure of the urban population still remained at the stage of formation. Different ethnic groups of the female urban population differed both in the rate and directions of selection. The migration of highlanders to the city mainly affected their mortality and morbidity, but not fecundity. The subpopulation of migrants from the highlands who retained a traditional endogamous and inbred marriage structure exhibited a high infant mortality comparable to that in the highland population. The migrant subpopulation in which interpopulation and interethnic marriages were contracted exhibited an increased genetic load expressed as high pre- and perinatal mortalities. The results obtained are discussed in terms of the hypotheses on the adaptive gene complex and the genetic and physiological mechanisms of differential adaptation of highland isolates to environmental changes due to migration or environmental pollution.

[Genetic polymorphism in three indigenous ethnic populations of Dagestan]. / Geneticheskii polimorfizm v trekh populiatsiiakh korennykh narodov Dagestana.

Genetic, demographic, and biochemical studies of three isolated ethnic populations of Dagestan were performed. Two populations lived in their historical (highland and lowland) habitats, and one population migrated from highlands to lowlands, i.e., changed its environment. A substantial genetic differentiation with respect to eight biochemical systems and marital structure was found. Altitudinal variation was revealed in allelic frequencies of group-specific component (GC) and haptoglobin (HP). The frequency of allele GC * 1 decreased and that of allele HP * 1 increased as the altitude increased in the studied localities. The studied populations differed with respect to the average heterozygosity levels per locus. Both absolute heterozygosity levels and the pattern of interpopulation differences estimated for all of the eight biochemical markers considerably differed from those estimated for all markers except for GC and HP. These data indicate that the latter two biochemical systems are important for adaptation of the studied Dagestan populations. In surviving migrants from highlands to lowlands, the levels of inbreeding and genetic polymorphism were intermediate between these values for highlanders and native lowlanders. Earlier, the 30% selective mortality was revealed in migrants from highlands to lowlands during the first years of adaptation to new conditions. Those individuals who died had a higher inbreeding level, homozygosity, and physiological sensitivity. In this study, only surviving migrants were examined. Therefore, it may be suggested that the inadaptive (dying) part of migrants also differed from the adaptive (surviving) part in the higher HP * 1 and GC * 2 allelic frequencies.