In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively ...analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others11Abbreviations: ADNI, Alzheimer's Disease Neuroimaging Initiative (http://www.adni-info.org); CHARGE, the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (http://www.chargeconsortium.com); IMAGEN, IMAging GENetics Consortium (http://www.imagen-europe.com)., ENIGMA's genomic screens – now numbering over 30,000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Isolated populations are valuable resources for mapping disease genes, as inbreeding increases genome-wide homozygosity and enhances the ability to map disease alleles on a genetically uniform ...background within a relatively homogenous environment. The populations of Daghestan are thought to have resided in the Caucasus Mountains for hundreds of generations and are characterized by a high prevalence of certain complex diseases. To explore the extent to which their unique population history led to increased levels of inbreeding, we genotyped >550 000 autosomal single-nucleotide polymorphisms (SNPs) in a set of 14 population isolates speaking Nakh-Daghestanian (ND) languages. The ND-speaking populations showed greatly elevated coefficients of inbreeding, very high numbers and long lengths of Runs of Homozygosity, and elevated linkage disequilibrium compared with surrounding groups from the Caucasus, the Near East, Europe, Central and South Asia. These results are consistent with the hypothesis that most ND-speaking groups descend from a common ancestral population that fragmented into a series of genetic isolates in the Daghestanian highlands. They have subsequently maintained a long-term small effective population size as a result of constant inbreeding and very low levels of gene flow. Given these findings, Daghestanian population isolates are likely to be useful for mapping genes associated with complex diseases.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Caucasus region is a complex cultural and ethnic mosaic, comprising populations that speak Caucasian, Indo-European and Altaic languages. Isolated mountain villages (auls) in Dagestan still ...preserve high level of genetic and cultural diversity and have patriarchal societies with a long history of isolation. The aim of this study was to understand the genetic history of five Dagestan highland auls with distinct ethnic affiliation (Avars, Chechens-Akkins, Kubachians, Laks, Tabasarans) using markers on the male-specific region of the Y chromosome. The groups analyzed here are all Muslims but speak different languages all belonging to the Nakh-Dagestanian linguistic family. The results show that the Dagestan ethnic groups share a common Y-genetic background, with deep-rooted genealogies and rare alleles, dating back to an early phase in the post-glacial recolonization of Europe. Geography and stochastic factors, such as founder effect and long-term genetic drift, driven by the rigid structuring of societies in groups of patrilineal descent, most likely acted as mutually reinforcing key factors in determining the high degree of Y-genetic divergence among these ethnic groups.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The present day distribution of Y chromosomes bearing the haplogroup J1 M267(*)G variant has been associated with different episodes of human demographic history, the main one being the diffusion of ...Islam since the Early Middle Ages. To better understand the modes and timing of J1 dispersals, we reconstructed the genealogical relationships among 282 M267(*)G chromosomes from 29 populations typed at 20 YSTRs and 6 SNPs. Phylogenetic analyses depicted a new genetic background consistent with climate-driven demographic dynamics occurring during two key phases of human pre-history: (1) the spatial expansion of hunter gatherers in response to the end of the late Pleistocene cooling phases and (2) the displacement of groups of foragers/herders following the mid-Holocene rainfall retreats across the Sahara and Arabia. Furthermore, J1 STR motifs previously used to trace Arab or Jewish ancestries were shown unsuitable as diagnostic markers for ethnicity.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To assess genetic diversity and genetic distances among isolated populations from Dagestan.
A cross-population genetic epidemiology design was applied in ethnically and demographically diverse ...isolates from Dagestan, some with more than 200 and some with less than 100 generations of demographical history since their founding.
The analysis of genetic diversity showed that Dagestan ethnic populations are clearly close to European ethnic populations. The genetic data support the view of them as ancient, highly isolated populations 85%-97% the rate of the endogamy and inbreeding coefficient F=0.010-0.015. Many Dagestan populations have very high prevalence of certain complex diseases such as cardiovascular illnesses, cancer, schizophrenia, mental retardation, and progressive muscular dystrophy. Lifetime morbid risk for schizophrenia in the isolates varied from 0 to 5%. Among the relatives, the number of men with chronic schizophrenia was at least twice as high as women. The average age of onset of schizophrenia was 21.2 years for offspring of consanguineous marriages and 17.4 years for offspring of non-consanguineous marriages (P=0.033).
The results support the hypothesis that cross-population design provides unique opportunities for observing reliable ancestral haplotypes with disease predisposing loci, as well as population-specific linked loci.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetic isolates are exceptional resources for the detection of susceptibility genes for complex diseases because of the potential reduction in genetic and clinical heterogeneity. However, the ...outcome of these mapping efforts is dependent upon the demographic history of a given isolated population, with the most significant factors being a constant population size, the number of generations since founding, and the pathogenic loci and their allele frequencies among founders. Here we employed a cross-isolate genome-wide multipoint linkage study design using uniform genetic and clinical methods in four Daghestan ethnically and demographically diverse isolates with an aggregation of schizophrenia. Our previous population-genetics study showed that Daghestan has an extremely high genetic diversity between ethnic populations and a low genetic diversity within them. The isolates selected for this study include some with more than 200 and some with fewer than 100 generations of demographical history since their founding. Updated clinical data using DSM-IV criteria showed between-isolate differences in aggregation of distinct types of schizophrenia: one of the isolates had a predominant aggregation of disorganized schizophrenia, while the other three had predominantly paranoid schizophrenia. The summarized cross-isolate results indicated prominent within and between-isolate differences in clinical and genetic heterogeneity: the most ancient isolates have roughly twofold fewer incidences of distinct clinical phenotypes and fewer linked genomic regions compared to the demographically younger isolates, which exhibit higher clinical and genetic heterogeneity. Affected individuals in the demographically ancient isolate of ethnic Dargins (No. 6022) who suffered from disorganized schizophrenia showed the highest linkage evidence at 17p11–p12 (LOD
=
3.73), while isolates with a predominant aggregation of paranoid schizophrenia (Nos. 6005, 6011, and 6034) showed the highest linkage evidence at 22q11 (LOD
=
3.0 and 4.4). The unified clinical, genomic, and statistical design we used enabled us to separate the linked and unlinked pedigrees in an unbiased fashion for each genomic location. Overall maximized heterogeneity lod scores for the combined pedigrees ranging from 3.5 to 8.7 were found at 2p24, 10q26, 11q23, 12q24, 17p11–p12, 22q11, and 22q13. The cross-isolate homogeneity in linkage patterns may be ascribed to an identical-by-descent “metahaplotype” block with pathogenic loci derived from the Daghestan ethnic groups’ common ancestral metapopulation, while the cross-isolate differences may reflect differences in gene drift and recombination events in the history of local isolates. The results obtained support the notion that mapping genes of any complex disease (e.g., schizophrenia) in demographically older genetic isolates may be more time and cost effective in comparison with demographically younger isolates, especially in genetically heterogeneous outbred populations, due to higher clinical and genetic homogeneity of the primary isolates. A study at higher genotyping density across the regions of interest and fluorescence in situ hybridization analyses are currently underway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We conducted a 10-cM genome-wide linkage scan in two extended pedigrees, ascertained from two diverse Dagestan genetic isolates with high aggregation of major depressive disorder (MDD) and suicides. ...Using genome wide multipoint parametric linkage analyses with short tandem repeat markers, we found two previously undetected genomic regions with significant linkage in isolate #6007 with LODs=3.1–3.4 at 2p13.2–p11.2 (and some signal in same region for #6008) and in 14q31.12–q32.13. We also obtained suggestive evidence for linkage with MDD at 9q33.3–q34.2 (#6008), 13q31.1–q31.2(#6007), 11p15(#6008), 17q25.3(#6007) and 19q13.31–q13.33 (#6008). Five regions (1p36.1–p35.2, 2p13.2–p11.2, 17q25.3, 18q22 and 22q12.3) demonstrated at least nominal linkage in both isolates’ pedigrees, while all other linkage regions demonstrated population-specific genetic heterogeneity.
While the season-of-birth effect is one of the most consistent epidemiological features of schizophrenia, there is a lack of consistency with respect to the interaction between season of birth and ...family history of schizophrenia. Apart from family history, measures related to consanguinity can be used as proxy markers of genomic heterogeneity. Thus, these measures may provide an alternate, indirect index of genetic susceptibility. We had the opportunity to explore the interaction between season of birth and measure of consanguinity in well-described genetic isolates in Daghestan, some of which are known for their relatively high prevalence of schizophrenia. Our previous population-genetic study showed Daghestan has an extremely high genetic diversity between the ethnic populations and a low genetic diversity within them. The isolates selected for this study include some with more than 200 and some with less than 100 generations of demographical history since their founding. Based on pedigrees of multiply-affected families, we found that among individuals with schizophrenia, the measure of consanguinity was significantly higher in the parents of those born in winter/spring compared to those born in summer/autumn. Furthermore, compared to summer/autumn born, winter/spring born individuals with schizophrenia had an earlier age-of-onset, and more prominent auditory hallucinations. Our results suggest that the offspring of consanguineous marriages, and thus those with reduced allelic heterogeneity, may be more susceptible to the environmental factor(s) underpinning the season-of-the effect in schizophrenia.
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