Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 47 (11), 1272-1281

Genome Sequencing Elucidates Sardinian Genetic Architecture and Augments Association Analyses for Lipid and Blood Inflammatory Markers


Genome Sequencing Elucidates Sardinian Genetic Architecture and Augments Association Analyses for Lipid and Blood Inflammatory Markers

Carlo Sidore et al. Nat Genet.


We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.


Figure 1
Figure 1. Geographical differentiation based on common and rare sites
The figure show allele sharing among the Sardinian and the 1000 Genomes European populations. In panel a) differentiation is represented for three different frequency intervals over the geographic map of Europe. The thickness and the color of the lines connecting the dots are proportional to the allele sharing statistic as indicated in the color map. In panel b) we instead represent the relationship between the frequency (X axis) and the sharing ratio (on the Y axis) for different 1000 Genomes Project populations (continuous lines). Results are plotted separately for the Lanusei valley sample (left panel) and the case control samples (right panel). The dotted line are used as comparison to show the sharing ratio between the TSI and other 1000 Genomes Project populations.
Figure 2
Figure 2. Length of shared haplotypes surrounding f2 variants within Sardinians and populations in 1000 Genomes
Length of shared haplotypes surrounding f2 variants shared between one of our sequenced individuals and one of 100 randomly selected individuals sampled from our study or from a particular 1000 Genomes Project population. Panel a) shows the length of these shared haplotypes, in kilobases, in comparisons between Sardinia and several 1000 Genomes Project populations. Panel b) shows the number of f2 haplotypes in each comparison. Panel c) shows the number of f2 haplotypes in comparisons within Sardinia (note the wider Y-axis range).
Figure 3
Figure 3. Regional association plots for novel lipids loci
Regional association plots at the HBB locus for LDL-c, and at APOA5 for triglycerides for imputation performed using the Sardinian (panels a and c) and 1000 Genomes (panels b and d) reference panels, respectively. At each locus, we plotted the association strength (Y axis shows the –log 10 pvalue) versus the genomic positions (on the hg19/GRCh37 genomic build) around the most significant SNP, which is indicated with a purple dot. Other SNPs in the region are color-coded to reflect their LD with the top SNP as in the inset (taken from pairwise r2 values calculated on Sardinian and 1000 Genomes haplotypes for left and right panels, respectively). Symbols reflect genomic functional annotation, as indicated in the inner box of panel A. Genes and the position of exons, as well as the direction of transcription, are noted in lower boxes. This plot was drawn using the standalone version of the LocusZoom package ().
Figure 4
Figure 4. Regional association plot at chromosome 12 for hSCRP and ESR
Regional association plots at the chromosome 12 locus for hsCRP and for ESR, using the Sardinian (panels a and c) and 1000 Genomes (panels b and d) reference panels for imputation, respectively. For the plot style, see Figure 3 legend.

Similar articles

See all similar articles

Cited by 67 articles

See all "Cited by" articles


    1. Parkes M, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat. Genet. 2007;39:830–832. - PMC - PubMed
    1. Willer CJ, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 2009;41:25–34. - PMC - PubMed
    1. Chen W, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2010;107:7401–7406. - PMC - PubMed
    1. Do R, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 2013;45:1345–1352. - PMC - PubMed
    1. Do R, Kathiresan S, Abecasis GR. Exome sequencing and complex disease: practical aspects of rare variant association studies. Hum. Mol. Genet. 2012;21:R1–9. - PMC - PubMed

Methods references

    1. Pruim RJ, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7. - PMC - PubMed
    1. Burdick JT, Chen W-M, Abecasis GR, Cheung VG. In silico method for inferring genotypes in pedigrees. Nat. Genet. 2006;38:1002–1004. - PMC - PubMed
    1. Voight BF, et al. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 2012;8:e1002793. - PMC - PubMed
    1. Parkes M, Cortes A, van Heel DA, Brown MA. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 2013;14:661–673. - PubMed
    1. Goldstein JI, et al. zCall: a rare variant caller for array-based genotyping: genetics and population analysis. Bioinforma. Oxf. Engl. 2012;28:2543–2545. - PMC - PubMed

Publication types

MeSH terms