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The ascertainment of multiplex schizophrenia pedigrees from Daghestan genetic isolates (Northern Caucasus, Russia).

ABSTRACT: This article describes the preliminary ascertainment of multiplex schizophrenia pedigrees from the isolated mountain region of Daghestan (Northern Caucasus, Russia). Daghestan has a population of two million people and contains 26 aboriginal ethnic groups. Many of the ethnic groups reside in remote mountain villages that can be classified as 'primary isolates'. Prolonged reproductive isolation and severe environmental conditions in the highlands have created diverse, genetically isolated ethnic populations in Daghestan. A number of the isolates in this region contain large extended multiplex schizophrenia pedigrees that are ideal for genetic analyses. During summer expeditions of 1996 and 1997, 14 separate large multiplex schizophrenia pedigrees were ascertained from 14 different mountain villages. Of the 14 kindreds, one had 50 schizophrenic cases available for ascertainment, one had 32, and another had 24. Seven of the remaining pedigrees had between 11 and 23 living cases. Within the kindreds, the number of males with chronic schizophrenia was at least twice that of females. The average age of onset of schizophrenia is 21.2 years for offspring of consanguineous marriages and 17.4 years for offspring of nonconsanguineous marriages (P = 0.033). Although the pedigrees ascertained from the remote mountain villages may not be representative of the general population, they are unique kindreds for mapping schizophrenia susceptibility genes.

SUBMITTER: Bulayeva KB

PROVIDER: S-EPMC6240907 | biostudies-other | 2000 Jun

REPOSITORIES: biostudies-other

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The ascertainment of multiplex schizophrenia pedigrees from Daghestan genetic isolates (Northern Caucasus, Russia).

Bulayeva K B KB Leal S M SM Pavlova T A TA Kurbanov R R Coover S S Bulayev O O Byerley W W

Psychiatric genetics 20000601 2

This article describes the preliminary ascertainment of multiplex schizophrenia pedigrees from the isolated mountain region of Daghestan (Northern Caucasus, Russia). Daghestan has a population of two million people and contains 26 aboriginal ethnic groups. Many of the ethnic groups reside in remote mountain villages that can be classified as 'primary isolates'. Prolonged reproductive isolation and severe environmental conditions in the highlands have created diverse, genetically isolated ethnic ...[more]

PMID: 10994643

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Project description:OBJECTIVE:The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD:The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS:No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10(-17), explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS:Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

Project description:BackgroundAutism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families.MethodsWe extracted from the Autism Genetic Resource Exchange (AGRE) database (n?=?3,818 children from 1,264 families) all families with relevant medical data (n?=?664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven's Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS).ResultsThe prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P?=?0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P?=?0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4).ConclusionsEpilepsy in multiplex autism may define a different subgroup in terms of clinical characteristics and genetic risk.

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The ascertainment of multiplex schizophrenia pedigrees from Daghestan genetic isolates (Northern Caucasus, Russia).

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The ascertainment of multiplex schizophrenia pedigrees from Daghestan genetic isolates (Northern Caucasus, Russia).

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