Investigation of the fine structure of European populations with applications to disease association studies

Abstract

An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East -West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North -South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies.

Demographic Events and Evolutionary Forces Shaping European Genetic Diversity

“…The only major genetic outliers were five Italian samples, which, based on later analyses, we now suspect are from Sardinia, an isolated island population in the Mediterranean (see below). At roughly the same time, other groups were finding similar results (Heath et al 2008;Lao et al 2008). The overall pattern to emerge from these studies of Europe is of a subtle genetic continuum among modern Europeans that is determined by geography.…”

Association of FGFR2 gene polymorphisms with the risk of breast cancer in population of West Siberia

“…These differences may reflect the history of the Russian population, which geographically lies between Western Europe and Asia and is known to form the ''eastern end'' of the European geographic and genetic distributions. 7 Although the LD pattern observed in our sample is similar to that observed in HapMap and other studies, the magnitude of LD in FGFR2 intron 2 generally seems to be lower in our population compared with that in the HapMap European population.…”

“…This finding may be explained by assuming that the LD structure in the Russian population resembles that of Europeans more closely than that of Asians, which is also consistent with recent studies of gene-geography. 7 Meyer et al 8 have recently shown that the haplotype marked by the minor allele of rs2981582 is associated with a higher level of FGFR2 transcription both in cell lines and in tumors. It was concluded that two SNPs, rs7895676 and rs2981578, located in the transcription factor binding sites (C/EBPb and Oct-1/Runx2) could affect the binding efficiency of these factors.…”

Fine-scale human genetic structure in Western France

“…[10][11][12] Evidence of population structure accumulates at the scale of European countries [13][14][15][16][17][18] and even at a finer scale. 19,20 Fine-scale genetic structure can result from different processes including founder effect, endogamy, historical migration, cultural barriers to gene flow or selection processes.…”