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Mapping genes of complex psychiatric diseases in Daghestan genetic isolates

Authors

  • Kazima B. Bulayeva,

    Corresponding author
    1. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
    2. Institute of History, Archeology, and Ethnology, Daghestan Research Center, Russian Academy of Sciences, Makhachkala, Daghestan, Russia
    • Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 117809 Russia.
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  • Suzanne M. Leal,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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  • Tatiana A. Pavlova,

    1. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
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  • Ruslan M. Kurbanov,

    1. Institute of History, Archeology, and Ethnology, Daghestan Research Center, Russian Academy of Sciences, Makhachkala, Daghestan, Russia
    2. Daghestan State Psychiatric Hospital, Makhachkala, Daghestan, Russia
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  • Stephen J. Glatt,

    1. Department of Psychiatry, University of California, San Diego, La Jolla, California
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  • Oleg A. Bulayev,

    1. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
    2. Institute of History, Archeology, and Ethnology, Daghestan Research Center, Russian Academy of Sciences, Makhachkala, Daghestan, Russia
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  • Ming T. Tsuang

    1. Department of Psychiatry, University of California, San Diego, La Jolla, California
    2. Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard Departments of Epidemiology and Psychiatry, Boston, Massachusetts
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Abstract

Genetic isolates, which provide outstanding opportunities for identification of susceptibility genes for complex diseases, can be classified as primary (having an ancient demographic history in a stable environment) or secondary (having a younger demographic history) Neel [1992: Minority populations: Genetics, demography, and health, pp. 1–13]. Daghestan contains 26 out of 50 indigenous Caucasus ethnicities that have been in existence for hundreds of generations in the same highland region. The ethnic groups are subdivided into numerous primary isolates. The founder effect and gene drift in these primary isolates may have caused aggregation of specific haplotypes with limited numbers of pathogenic alleles and loci in some isolates relative to others. These are expressed as inter-population differences in lifetime prevalence and features of certain complex clinical phenotypes and in patterns of genetic linkage and linkage disequilibrium (LD). Stable highland and ethnic-cultural environments have led to increased penetrance and a reduced number of phenocopies, which typically hamper the identification of any susceptibility genes for complex diseases. Owing to these characteristics of the primary isolates, a comparative linkage study in the primary isolates allows us to define the number of susceptibility genes for any complex disease and to identify the source of variability and non-replication of linkage analysis results. As part of an ongoing study, seven extended schizophrenia and one nonspecific mental retardation kindreds have been ascertained from Daghestan isolates. Lifetime morbid risk for schizophrenia in the isolates varied from 0 to 5%. A genome scan with markers spaced 10 cM apart was carried out on these pedigrees and linkage analysis was performed using descent graph methods, as implemented in Simwalk2. To identify regions containing susceptibility genes within these kindreds, we followed up those regions with non-parametric and parametric linkage analyses, with the choice of genetic model guided by the results obtained in the NPL. While the analyses are ongoing, the most positive findings were made in different isolated pedigrees on chromosomes 17p11, 3q24, and 22q for schizophrenia and on chromosome 12q for nonspecific mental retardation. © 2004 Wiley-Liss, Inc.

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