Genomic structural variants are linked with intellectual disability

Mutations in more than 500 genes have been associated with intellectual disability (ID) and related disorders of cognitive function, such as autism and schizophrenia. Here we aimed to unravel the molecular epidemiology of non-specific ID in a genetic isolate using a combination of population and molecular genetic approaches. A large multigenerational pedigree was ascertained within a Dagestan Genetic Heritage research program in a genetic isolate of indigenous ethnics. Clinical characteristics of the affected members were based on combining diagnoses from regional psychiatric hospitals with our own clinical assessment, using a Russian translation of the structured psychiatric interviews, the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies, based on DSM-IV criteria. Weber/CHLC 9.0 STRs set was used for multipoint parametric linkage analyses (Simwalk2.91). Next, we checked CNVs and LOH (based on Affymetrix SNP 5.0 data) in the linked with ID genomic regions with the aim to identify candidate genes associated with mutations in linked regions. The number of statistically significant (p ≤ 0.05) suggestive linkage peaks with 1.3 3 were obtained at 2p25.3-p24.2 under the dominant model, with a peak at 21 cM flanked by loci D2S2976 and D2S2952; at 12q24.22-q24.31 under the recessive model, with a peak at -120 cM flanked by marker D12S2070 and D12S395 and at 22q12.3 under the dominant model, with a peak at 32 cM flanked by marker D22S683 and D22S445. After a set of genes had been designated as possible candidates in these specific chromosomal regions,we conducted an exploratory search for LOH and CNV based on microarray data to detect structural genomic variants within five ID-linked regions with LOD scores between 2.0 and 3.9. In these selected regions we obtained 173 ROH segments and 98 CN segments. Further analysis of region 2p25.3-p24.2 revealed deletions within genes encoding MYTL, SNTG2 and TPO among five of 21 affected cases at 2p25.3-p24.2. In the ID-linked region at 12q24.22-12q24.31 19 out of 21 ID cases carried segmental CNV and 20 of 21 them displayed ROH segments with mean size lengths for ID cases 2512 kb (500-6,472 kb) and for healthy control 682 kb (531-986 kb), including the genes MED13L, HRK, FBXW8, TESC, CDK2AP1 and SBNO1. Seven of 21 affected pedigree members displayed segmental deletions at 22q12.3 that includes the gene LARGE. Eight affected pedigree members carried ROH segments and 6 CN segments at 10p11.23-p11.21 containing the genes ZEB1, c10orf68 and EPC1. Our linkage and structural genomic variation analyses in a remote highland genetic isolate with aggregation of ID demonstrated that even highly isolated single kindred ID has oligo/polygenic pathogenesis. The results obtained implicate 10 genomic regions linked with ID that contain some of previously reported candidate genes, including HRK, FBXW8, TESC, CDK2AP1 and SBNO1 at 12q24 that were shown in recent studies as associated with brain measures derived from MRI scans

Coevolution of genes and languages and high levels of population structure among the highland populations of Daghestan.

As a result of the combination of great linguistic and cultural diversity, the highland populations of Daghestan present an excellent opportunity to test the hypothesis of language-gene coevolution at a fine geographic scale. However, previous genetic studies generally have been restricted to uniparental markers and have not included many of the key populations of the region. To improve our understanding of the genetic structure of Daghestani populations and to investigate possible correlations between genetic and linguistic variation, we analyzed ~550,000 autosomal single nucleotide polymorphisms, phylogenetically informative Y chromosome markers and mtDNA haplotypes in 21 ethnic Daghestani groups. We found high levels of population structure in Daghestan consistent with the hypothesis of long-term isolation among populations of the highland Caucasus. Highland Daghestani populations exhibit extremely high levels of between-population diversity for all genetic systems tested, leading to some of the highest FST values observed for any region of the world. In addition, we find a significant positive correlation between gene and language diversity, suggesting that these two aspects of human diversity have coevolved as a result of historical patterns of social interaction among highland farmers at the community level. Finally, our data are consistent with the hypothesis that most Daghestanian-speaking groups descend from a common ancestral population (~6000-6500 years ago) that spread to the Caucasus by demic diffusion followed by population fragmentation and low levels of gene flow

Mapping Genes Related to Early Onset Major Depressive Disorder in Dagestan Genetic Isolates 2) who genotyped AFFX SNP 6 in selected MDD cases

SUMMARY Aim: 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. Methods: 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. Results: 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. Conclusion: 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