Fine-Scale Population Structure in Europe. S. Leslie1, G. Hellenthal2, S. Myers3, P. Donnelly3, 4, International Multiple Sclerosis Genetics Consortium 1) Statistical Genetics, Murdoch Childrens Research Institute, Parkville, Victoria, Australia; 2) University College London Genetics Institute, Darwin Building, Gower Street, London, WC1E 6BT, UK; 3) University of Oxford, Department of Statistics, 1 South Parks Road, Oxford, OX1 3TG, UK; 4) The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK.

   There is considerable interest in detecting and interpreting fine-scale population structure in Europe: as a signature of major events in the history of the populations of Europe, and because of the effect undetected population structure may have on disease association studies. Population structure appears to have been a minor concern for most of the recent generation of genome-wide association studies, but is likely to be important for the next generation of studies seeking associations to rare variants. Thus far, genetic studies across Europe have been limited to a small number of markers, or to methods that do not specifically account for the correlation structure in the genome due to linkage disequilibrium. Consequently, these studies were unable to group samples into clusters of similar ancestry on a fine (within country) scale with any confidence. We describe an analysis of fine-scale population structure using genome-wide SNP data on 6,209 individuals, sampled mostly from Western Europe. Using a recently published clustering algorithm (fineSTRUCTURE), adapted for specific aspects of our analysis, the samples were clustered purely as a function of genetic similarity, without reference to their known sampling locations. When plotted on a map of Europe one observes a striking association between the inferred clusters and geography. Interestingly, for the most part modern country boundaries are significant i.e. we see clear evidence of clusters that exclusively contain samples from a single country. At a high level we see: the Finns are the most differentiated from the rest of Europe (as might be expected); a clear divide between Sweden/Norway and the rest of Europe (including Denmark); and an obvious distinction between southern and northern Europe. We also observe considerable structure within countries on a hitherto unseen fine-scale - for example genetically distinct groups are detected along the coast of Norway. Using novel techniques we perform further analyses to examine the genetic relationships between the inferred clusters. We interpret our results with respect to geographic and linguistic divisions, as well as the historical and archaeological record. We believe this is the largest detailed analysis of very fine-scale human genetic structure and its origin within Europe. Crucial to these findings has been an approach to analysis that accounts for linkage disequilibrium.

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