Caratterizzazione molecolare di tratti quantitativi di potenziale interesse biomedico nella popolazione sarda - studio SardiNIA

The thesis describes in three examples of GWAS conducted in the contest of the SardiNIA study using a Whole Genome Sequenced based GWAS with the purpose of explaining the missing heritability for these traits and with the aim to characterize quantitative traits of potential biomedical interest in the Sardinian population.In the study 6,807 individuals from Ogliastra region were recruited, phenotyped. Subsequently all individuals were genotyped with four Illumina arrays to create a scaffold of 890,542 variants to imput 17 million variants from a reference panel of 2,210 unrelated individuals from a low pass sequencing data, to the entire cohort using haplotype blocks shared by all Sardinian individuals.GWAS analysis revealed 2 new loci associated with LDL and total cholesterol in the HBB, LDLR genes and one variant in APOA5 gene for triglycerides. Among haematologic traits for hemoglobin A1, A2 and F levels we found: 5 association signals mapping at new loci MPHOSPH9, PLTP-PCIF1, FOG1, NFIX and CCND3.Therefore 10 new variants and 4 independent signals were detected during fine mapping of the known loci. For anthropometric traits we report two signals with a strong effect on stature located in GHR and KCNQ1 genes. Conclusions: The results indicate a sequencing-based GWAS as a robust methodology to investigate the missing heritability leading to complex trait dissection. Many of variants we describe are Sardinian specific and of potential pharmaceutical interest.