Pitzalis, Maristella (2012) La Sclerosi Multipla: approcci per identificare loci coinvolti nella patogenesi: sequenziamento low-pass e studio di associazione su tutto il genoma in Sardegna. Doctoral Thesis.
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To find new genetic associations with Multiple sclerosis (MS), a multifactorial neuroinflammatory autoimmune disorder, very common in Sardinia, we performed a genome wide association scan (GWAS) in 882 unrelated Sardinian MS cases and 872 controls genotyped with the Affymetrix 6.0 array. We found one novel gene, CBLB, associated with MS (p = 1.60x10-10 in 2,657 cases and 2,877 controls).
Following, we performed a GWAS in 2280 cases and 1920 controls. All samples were typed with the 6.0 array and a subset of 837, also with the Illumina 1 M Duo array. To enrich for rare variants, we performed imputation using low-pass sequencing data from 505 Sardinians, or 280 Europeans of the 1000 Genomes project.
Imputation with the Sardinian reference panel worked better than with the 1000 Genome panel, particularly when data from more samples was used. A greater number of SNPs passed quality filters and with higher imputation quality ratings, especially for rare variants (mean RSQR 0.92 vs 0.75).
We selected some variants to be followed up with TaqMan genotyping. We confirmed the HLA region and CD58, IL2RA, CLEC16A, IRF8, CBLB, TNFRSF14 loci, and some new loci identified by the International MS Consortium.
In conclusion, we found the CBLB gene associated with MS and that the imputation method benefited from using sequencing data from the same population. Next, the sequencing data from ~1200 Sardinians and ImmunoChip data of 3200 cases and 4500 controls will be used to detect novel MS loci.
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