A genome-wide analysis of Sardinian population structure

Sardinia is particular attractive for human genetic studies, being one of the larger isolated populations and thus suitable for large-scale studies. Several attempts have been made to explore its genetic structure, but they either analyzed a large set of markers in very few samples or thousands of individuals at specific loci. Here we genotyped 2,615 individuals with the Affymetrix 6.0 array. Samples were recruited from the north, south and central east areas of the Island, and initially considered as 3 distinct populations. Genotype calling was performed with Birdseed-v2, considering all samples as a unique cluster to avoid batch effects. Subsequently, we applied standard filters for samples and SNP quality, and used IBD sharing to detect, and discard, hidden relatives. Using principal component analysis, we identified outliers and reassigned each individual accordingly. An analysis of molecular variance indicated that only 0.21% of the variability could be attributable to inter-population variation (Fst=0.002), confirming a lack of large-scale substructure. We thus considered the Sardinians as a unique sample. Compared to HapMap3 populations, as expected, higher similarity was observed with Tuscany and CEPH samples (Fst=0.005 and 0.010, respectively). A genome-wide search for SNPs highly differentiated between Sardinians and these European populations confirmed the specialness of HLA and LCT regions, and also showed elevated Fst values (>0.27) at the CR1 gene, known to be related to malaria severity. We are now integrating sequencing data of many individuals to provide a more comprehensive analysis of variants in addition to the common SNPs in current genotyping platform.