Detecting the Sardinian specific variability trough next generation sequencing of 2120 individuals

Aim: Genome-wide association studies may not capture the fraction of genome variation that is rare or unique to specific populations. Sequencing projects can overcome these limitations. The goal of this work is to generate a Sardinian sequencing panel to analyse 1) a sample of >6,000 individuals from Ogliastra to study a variety of quantitative traits and 2) a case control collection of 8000 individuals collected across Sardinia to dissect the genetic of autoimmunity.Methods: Using whole genome sequencing, we sequenced 2,120 Sardinians enrolled in these projects, at a mean depth of 4X. We imputed these data on high-density micro-arrays genotyped in all 15000 samples.Results: We successfully identified and genotyped >17M single nucleotide polymorphisms with an error rate of 0.2%. To increase the power to detect association, we are using the haplotypes generated by sequencing of these individuals to impute missing genotypes in the remaining >14000 already genotyped. Strikingly, imputation using our Sardinian reference panel shows increased accuracy when compared to an equal size reference panel of European haplotypes generated by the 1000 Genomes Project. As an example of the advantages of analyzing population specific rare variation, we will discuss the Q40X mutation in the HBB gene, common in Sardinia (MAF ~5%) but very rare elsewhere, and its effects on LDL cholesterol levels.Conclusion: Our approach thus increases the resolution of analysis of genomic variation and allows the detection of population specific variants.