Publications (13)74.21 Total impact
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Article: Exploring Genomic Structure Differences and Similarities between the Greek and European HapMap Populations: Implications for Association Studies.
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ABSTRACT: Studies of the genomic structure of the Greek population and Southeastern Europe are limited, despite the central position of the area as a gateway for human migrations into Europe. HapMap has provided a unique tool for the analysis of human genetic variation. Europe is represented by the CEU (Northwestern Europe) and the TSI populations (Tuscan Italians from Southern Europe), which serve as reference for the design of genetic association studies. Furthermore, genetic association findings are often transferred to unstudied populations. Although initial studies support the fact that the CEU can, in general, be used as reference for the selection of tagging SNPs in European populations, this has not been extensively studied across Europe. We set out to explore the genomic structure of the Greek population (56 individuals) and compare it to the HapMap TSI and CEU populations. We studied 1112 SNPs (27 regions, 13 chromosomes). Although the HapMap European populations are, in general, a good reference for the Greek population, regions of population differentiation do exist and results should not be light-heartedly generalized. We conclude that, perhaps due to the individual evolutionary history of each genomic region, geographic proximity is not always a perfect guide for selecting a reference population for an unstudied population.Annals of Human Genetics 11/2012; 76(6):472-483. · 2.57 Impact Factor -
Article: G894T polymorphism of eNOS gene is a predictor of response to combination of inhaled corticosteroids with long-lasting β(2)-agonists in asthmatic children.
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ABSTRACT: Aim: Nitric oxide synthase enzymes have an important role in airway inflammation in asthmatic children. In the present study, the association between eNOS gene polymorphisms and response to inhaled corticosteroids (ICS) and long-lasting β(2)-agonists (LABAs) was investigated. Patients & methods: A total of 81 asthmatic children treated with ICS plus LABAs and 96 healthy controls were genotyped for eNOS G894T and -786T/C polymorphisms and their haplotypes using the PCR-RFLP method. Results: G894T and -786T/C polymorphisms were not associated with asthma susceptibility. Among asthmatic children, 894TT carriers had higher change in forced expiratory volume in 1 s (FEV(1)) in response to ICS plus LABAs compared with 894GG carriers (21.9 ± 3.8 vs 1.6 ± 1.9%; p < 0.001). In responders (FEV(1) change ≥7.5%), frequency of 894TT genotype was significantly higher than in nonresponders (26.2 vs 2.6%, p < 0.001). Results for the -786T/C polymorphism alone were less clear and in most cases nonsignificant. Conclusion: The G894T polymorphism was associated with response to ICS and may serve as a useful pharmacogenetic marker of response to ICS plus LABAs in asthmatic children. Original submitted 10 May 2012; Revision submitted 13 July 2012.Pharmacogenomics 09/2012; 13(12):1363-72. · 3.97 Impact Factor -
Article: A global view of the OCA2-HERC2 region and pigmentation.
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ABSTRACT: Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.Human Genetics 11/2011; 131(5):683-96. · 5.07 Impact Factor -
Article: Efficient genomewide selection of PCA-correlated tSNPs for genotype imputation.
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ABSTRACT: The linkage disequilibrium structure of the human genome allows identification of small sets of single nucleotide polymorphisms (SNPs) (tSNPs) that efficiently represent dense sets of markers. This structure can be translated into linear algebraic terms as evidenced by the well documented principal components analysis (PCA)-based methods. Here we apply, for the first time, PCA-based methodology for efficient genomewide tSNP selection; and explore the linear algebraic structure of the human genome. Our algorithm divides the genome into contiguous nonoverlapping windows of high linear structure. Coupling this novel window definition with a PCA-based tSNP selection method, we analyze 2.5 million SNPs from the HapMap phase 2 dataset. We show that 10-25% of these SNPs suffice to predict the remaining genotypes with over 95% accuracy. A comparison with other popular methods in the ENCODE regions indicates significant genotyping savings. We evaluate the portability of genome-wide tSNPs across a diverse set of populations (HapMap phase 3 dataset). Interestingly, African populations are good reference populations for the rest of the world. Finally, we demonstrate the applicability of our approach in a real genome-wide disease association study. The chosen tSNP panels can be used toward genotype imputation using either a simple regression-based algorithm or more sophisticated genotype imputation methods.Annals of Human Genetics 09/2011; 75(6):707-22. · 2.57 Impact Factor -
Article: Tracing cattle breeds with principal components analysis ancestry informative SNPs.
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ABSTRACT: The recent release of the Bovine HapMap dataset represents the most detailed survey of bovine genetic diversity to date, providing an important resource for the design and development of livestock production. We studied this dataset, comprising more than 30,000 Single Nucleotide Polymorphisms (SNPs) for 19 breeds (13 taurine, three zebu, and three hybrid breeds), seeking to identify small panels of genetic markers that can be used to trace the breed of unknown cattle samples. Taking advantage of the power of Principal Components Analysis and algorithms that we have recently described for the selection of Ancestry Informative Markers from genomewide datasets, we present a decision-tree which can be used to accurately infer the origin of individual cattle. In doing so, we present a thorough examination of population genetic structure in modern bovine breeds. Performing extensive cross-validation experiments, we demonstrate that 250-500 carefully selected SNPs suffice in order to achieve close to 100% prediction accuracy of individual ancestry, when this particular set of 19 breeds is considered. Our methods, coupled with the dense genotypic data that is becoming increasingly available, have the potential to become a valuable tool and have considerable impact in worldwide livestock production. They can be used to inform the design of studies of the genetic basis of economically important traits in cattle, as well as breeding programs and efforts to conserve biodiversity. Furthermore, the SNPs that we have identified can provide a reliable solution for the traceability of breed-specific branded products.PLoS ONE 01/2011; 6(4):e18007. · 4.09 Impact Factor -
Article: Ancestry informative markers for fine-scale individual assignment to worldwide populations.
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ABSTRACT: The analysis of large-scale genetic data from thousands of individuals has revealed the fact that subtle population genetic structure can be detected at levels that were previously unimaginable. Using the Human Genome Diversity Panel as reference (51 populations - 650,000 SNPs), this works describes a systematic evaluation of the resolution that can be achieved for the inference of genetic ancestry, even when small panels of genetic markers are used. A comprehensive investigation of human population structure around the world is undertaken by leveraging the power of Principal Components Analysis (PCA). The problem is dissected into hierarchical steps and a decision tree for the prediction of individual ancestry is proposed. A complete leave-one-out validation experiment demonstrates that, using all available SNPs, assignment of individuals to their self-reported populations of origin is essentially perfect. Ancestry informative genetic markers are selected using two different metrics (In and correlation with PCA scores). A thorough cross-validation experiment indicates that, in most cases here, the number of SNPs needed for ancestry inference can be successfully reduced to less than 0.1% of the original 650,000 while retaining close to 100% accuracy. This reduction can be achieved using a novel clustering-based redundancy removal algorithm that is also introduced here. Finally, the applicability of our suggested SNP panels is tested on HapMap Phase 3 populations. The proposed methods and ancestry informative marker panels, in combination with the increasingly more comprehensive databases of human genetic variation, open new horizons in a variety of fields, ranging from the study of human evolution and population history, to medical genetics and forensics.Journal of Medical Genetics 10/2010; 47(12):835-47. · 6.36 Impact Factor -
Article: Genetic variation in the visfatin (PBEF1/NAMPT) gene and type 2 diabetes in the Greek population.
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ABSTRACT: Visfatin (NAMPT formerly known as PBEF1) is an adipokine that is strongly expressed in visceral fat and has caused much debate among researchers, regarding its involvement in glucose homeostasis and insulin resistance. It was initially isolated from bone marrow cells, and its involvement in inflammatory procedures such as sepsis and acute lung inflammation is now evident. Several studies have also reported an association of plasma visfatin levels with obesity. We undertook an evaluation of the involvement of the NAMPT gene in the development of type 2 diabetes (T2DM) in the Greek population. We studied 178 patients with T2DM and 177 controls that were matched for sex, age and body mass index. We genotyped three tagging SNPs selected from the HapMap II CEPH European population as reference for the Greek population. These three SNPs tag another 12 SNPs over the entire NAMPT gene with a mean r(2) of 0.92. No indications of association with disease status were found with any of the tested variants or the inferred haplotypes. Results were also negative when the quantitative traits of weight and BMI were tested. Although our study covers common variants across the NAMPT gene, the possible involvement of rare variants in T2DM etiology cannot be ruled out and will require the investigation of very large numbers of cases and controls.Cytokine 07/2010; 51(1):25-7. · 3.02 Impact Factor -
Article: The distribution and most recent common ancestor of the 17q21 inversion in humans.
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ABSTRACT: The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an approximately 900 kb inversion found primarily in Europeans and Southwest Asians. We have identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of approximately 30%); elsewhere in Europe, frequencies vary from < 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the approximately 900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.The American Journal of Human Genetics 02/2010; 86(2):161-71. · 10.60 Impact Factor -
Article: Inferring geographic coordinates of origin for Europeans using small panels of ancestry informative markers.
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ABSTRACT: Recent large-scale studies of European populations have demonstrated the existence of population genetic structure within Europe and the potential to accurately infer individual ancestry when information from hundreds of thousands of genetic markers is used. In fact, when genomewide genetic variation of European populations is projected down to a two-dimensional Principal Components Analysis plot, a surprising correlation with actual geographic coordinates of self-reported ancestry has been reported. This substructure can hamper the search of susceptibility genes for common complex disorders leading to spurious correlations. The identification of genetic markers that can correct for population stratification becomes therefore of paramount importance. Analyzing 1,200 individuals from 11 populations genotyped for more than 500,000 SNPs (Population Reference Sample), we present a systematic exploration of the extent to which geographic coordinates of origin within Europe can be predicted, with small panels of SNPs. Markers are selected to correlate with the top principal components of the dataset, as we have previously demonstrated. Performing thorough cross-validation experiments we show that it is indeed possible to predict individual ancestry within Europe down to a few hundred kilometers from actual individual origin, using information from carefully selected panels of 500 or 1,000 SNPs. Furthermore, we show that these panels can be used to correctly assign the HapMap Phase 3 European populations to their geographic origin. The SNPs that we propose can prove extremely useful in a variety of different settings, such as stratification correction or genetic ancestry testing, and the study of the history of European populations.PLoS ONE 01/2010; 5(8):e11892. · 4.09 Impact Factor -
Article: Tracing sub-structure in the European American population with PCA-informative markers.
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ABSTRACT: Genetic structure in the European American population reflects waves of migration and recent gene flow among different populations. This complex structure can introduce bias in genetic association studies. Using Principal Components Analysis (PCA), we analyze the structure of two independent European American datasets (1,521 individuals-307,315 autosomal SNPs). Individual variation lies across a continuum with some individuals showing high degrees of admixture with non-European populations, as demonstrated through joint analysis with HapMap data. The CEPH Europeans only represent a small fraction of the variation encountered in the larger European American datasets we studied. We interpret the first eigenvector of this data as correlated with ancestry, and we apply an algorithm that we have previously described to select PCA-informative markers (PCAIMs) that can reproduce this structure. Importantly, we develop a novel method that can remove redundancy from the selected SNP panels and show that we can effectively remove correlated markers, thus increasing genotyping savings. Only 150-200 PCAIMs suffice to accurately predict fine structure in European American datasets, as identified by PCA. Simulating association studies, we couple our method with a PCA-based stratification correction tool and demonstrate that a small number of PCAIMs can efficiently remove false correlations with almost no loss in power. The structure informative SNPs that we propose are an important resource for genetic association studies of European Americans. Furthermore, our redundancy removal algorithm can be applied on sets of ancestry informative markers selected with any method in order to select the most uncorrelated SNPs, and significantly decreases genotyping costs.PLoS Genetics 08/2008; 4(7):e1000114. · 8.69 Impact Factor -
Article: PCA-correlated SNPs for structure identification in worldwide human populations.
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ABSTRACT: Existing methods to ascertain small sets of markers for the identification of human population structure require prior knowledge of individual ancestry. Based on Principal Components Analysis (PCA), and recent results in theoretical computer science, we present a novel algorithm that, applied on genomewide data, selects small subsets of SNPs (PCA-correlated SNPs) to reproduce the structure found by PCA on the complete dataset, without use of ancestry information. Evaluating our method on a previously described dataset (10,805 SNPs, 11 populations), we demonstrate that a very small set of PCA-correlated SNPs can be effectively employed to assign individuals to particular continents or populations, using a simple clustering algorithm. We validate our methods on the HapMap populations and achieve perfect intercontinental differentiation with 14 PCA-correlated SNPs. The Chinese and Japanese populations can be easily differentiated using less than 100 PCA-correlated SNPs ascertained after evaluating 1.7 million SNPs from HapMap. We show that, in general, structure informative SNPs are not portable across geographic regions. However, we manage to identify a general set of 50 PCA-correlated SNPs that effectively assigns individuals to one of nine different populations. Compared to analysis with the measure of informativeness, our methods, although unsupervised, achieved similar results. We proceed to demonstrate that our algorithm can be effectively used for the analysis of admixed populations without having to trace the origin of individuals. Analyzing a Puerto Rican dataset (192 individuals, 7,257 SNPs), we show that PCA-correlated SNPs can be used to successfully predict structure and ancestry proportions. We subsequently validate these SNPs for structure identification in an independent Puerto Rican dataset. The algorithm that we introduce runs in seconds and can be easily applied on large genome-wide datasets, facilitating the identification of population substructure, stratification assessment in multi-stage whole-genome association studies, and the study of demographic history in human populations.PLoS Genetics 10/2007; 3(9):1672-86. · 8.69 Impact Factor -
Article: Intra- and interpopulation genotype reconstruction from tagging SNPs.
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ABSTRACT: The optimal method to be used for tSNP selection, the applicability of a reference LD map to unassayed populations, and the scalability of these methods to genome-wide analysis, all remain subjects of debate. We propose novel, scalable matrix algorithms that address these issues and we evaluate them on genotypic data from 38 populations and four genomic regions (248 SNPs typed for approximately 2000 individuals). We also evaluate these algorithms on a second data set consisting of genotypes available from the HapMap database (1336 SNPs for four populations) over the same genomic regions. Furthermore, we test these methods in the setting of a real association study using a publicly available family data set. The algorithms we use for tSNP selection and unassayed SNP reconstruction do not require haplotype inference and they are, in principle, scalable even to genome-wide analysis. Moreover, they are greedy variants of recently developed matrix algorithms with provable performance guarantees. Using a small set of carefully selected tSNPs, we achieve very good reconstruction accuracy of "untyped" genotypes for most of the populations studied. Additionally, we demonstrate in a quantitative manner that the chosen tSNPs exhibit substantial transferability, both within and across different geographic regions. Finally, we show that reconstruction can be applied to retrieve significant SNP associations with disease, with important genotyping savings.Genome Research 02/2007; 17(1):96-107. · 13.61 Impact Factor -
Article: HLA alleles and type 1 diabetes mellitus in low disease incidence populations of Southern Europe: a comparison of Greeks and Albanians.
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ABSTRACT: Type 1 diabetes mellitus (DM1) is caused by environmental factors acting on genetically susceptible individuals. HLA-DQA1 and -DQB1 are major genetic determinants of the disease. Greece and Albania represent the low DM1 incidence countries of South-Eastern Europe. The HLA-DQA1 and -DQB1 associations with DM1 were investigated in these two groups, as reference for comparisons to the high-risk populations of Northern Europe. One hundred and thirty Greeks and 64 Albanians with DM1 were studied; 1,842 Greeks and 186 Albanians were analysed as controls. The samples were typed for six HLA-DQB1 alleles, using time-resolved fluorometry to detect the hybridisation of lanthanide labelled oligonucleotides with PCR products. Individuals positive for DQB1*0201 were selectively typed for three DQA1 alleles. In both populations DQB1*0201 increased the risk for DM1 while DQB1*0301 was protective. DQB1*0302 was associated with lower risk than *0201, while *0602 and *0603 were protective in Greeks but not in Albanians. It was also shown that DQA1 has a modifying effect, altering the risk conferred by the susceptible DQB1*0201. The low incidence of DM1 in these two countries correlates with the high frequency of the protective allele DQB1*0301 and the low impact of the susceptible DQB1*0302.Journal of pediatric endocrinology & metabolism: JPEM 03/2004; 17(2):173-82. · 0.88 Impact Factor
Top co-authors
Top Journals
Institutions
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2010–2011
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Rensselaer Polytechnic Institute
Troy, NY, USA
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2007–2010
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Democritus University of Thrace
- Tμήμα Μοριακής Βιολογίας και Γενετικής
Komotiní, Anatoliki Makedonia kai Thraki, Greece -
Yale University
- Department of Genetics
New Haven, CT, USA
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