TARTU ÜLIKOOL LOODUS JA TEHNOLOOGIA TEADUSKOND MOLEKULAAR- JA RAKUBIOLOOGIA INSTITUUT

Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was . 100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Centraland Western Europe in its centre. Interand intrapopulation genetic differences were quantified by the inflation factor lambda (l) (ranging from 1.00 to 4.21), fixation index (Fst) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS). PLoS ONE | www.plosone. org 1 May 2009 | Volume 4 | Issue 5 | e5472 Citation: Nelis M, Esko T, Mägi R, Zimprich F, Zimprich A, et al. (2009) Genetic Structure of Europeans: A View from the North–East. PLoS ONE 4(5): e5472. doi:10.1371/journal.pone. 0005472 Editor: Robert C. Fleischer, Smithsonian Institution National Zoological Park, United States of America Received January 29, 2009; Accepted March 26, 2009; Published May 8, 2009 Copyright: 2009 Nelis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This research was supported by the EU European Regional Development Fund through the Centre of Excellence in Genomics, Estonian Biocentre and University of Tartu. MN, TE and AM were supported by Enterprise Estonia project EU19955 and by the Estonian Ministry of Education and Research grant 0180142s08. RM was financed through European Commission grant 205419 (ECOGENE) to Estonian Biocentre and EU FP6 project ‘‘LifeSpan’’. RM and MR were also supported by the Estonian Ministry of Education and Research grant 0182649s04. Part of the financing came from the EU funded ENGAGE project (grant 201413) of the FP7. DToncheva and SK were supported by the ‘‘Characterization of the anthropo-genetic identity of Bulgarians’’ Project of the Bulgarian Ministry of Education and Science, reference No. TK01-487/16.06. 2008. LP was funded by the Center of Excellence in Common Disease Genetics of the Academy of Finland. RR is a ‘‘Ramon y Cajal’’ postdoctoral fellow supported by the Spanish Ministry of Science and Innovation. MM was supported by grants VZFNM00064203 and NS NS9488/3 provided by the Ministry of Health of the Czech Republic. Research on the French sample has been supported by the French Ministry of Higher Education and Research. Research on samples from Northern Italy has been supported by the Compagnia di San Paolo Foundation and Health Ministry grant PSCARDIO ex 56//05/7. Research on the Spanish sample has been supported by grants from the Spanish Ministry of Science and Innovation (SAF2008-00357 to XE and PSE-01000-2006-6 to SM), ENGAGE (FP7/2007-201413) and AnEUploidy (FP6/2006-037627) EU grants to XE. The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. The work of KORA is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus). Swiss sample provision has been supported by grants from the National Science Foundation, Infectigen Foundation, and AnEUploidy EU IP (037627) grants to SEA. Research on the Latvian sample has been supported by Ministry of Health, Republic of Latvia (agreement No. 3308/IGDB-1/2008). This research was also supported by the Russian Academy of Sciences, Program ‘‘Molecular and Cell Biology’’, and the Russian Basic Research Foundation. The study has also been supported by a research grant of the Italian Ministry of Health (Ricerca Corrente 2007 and Ricerca Finalizzata Cardiovascolare). Competing Interests: The authors have declared that no competing interests exist. * E-mail: andres@ebc.ee . These authors contributed equally to this work.