Multiple sclerosis (MS) is a complex disorder characterized by myelin damage and neurodegeneration. Until now 103 susceptibility genetic loci have been identified through genome-wide association studies (GWAS), however they involved samples from several different countries that could have a different genetic and environmental predisposition. The aim of the present project was to identify and characterise the most associated regions in the Italian population following a multi-step approach. We started from 2 cohorts of Italian continental MS patients and healthy controls (HC): ITAGWAS (750 MS, 1291 HC) with available imputed genome-wide genotypes and ITAiChip (977 MS, 986 HC) with genotyping data in 184 immune regions. To boost the statistical power of the study, the top associated signals of association (p< 0.005) in the two Italian cohorts were meta-analysed with an imputation-based meta-analysed cohort of 20,512 cases and 19,145 HC of European ancestry from USA. A total of 16 loci of association were identified (p< 5x10-7) and then tested for an association in a third Italian cohort (903 MS, 884 HC). This replication phase confirmed the association of two loci on chromosome 17 and chromosome 3, already known to be associated with the disease. To better characterize them we next sequenced them in an Italian cohort of 600 MS and 408 HC using a pooling approach and comparing high-risk MS patients and low-risk HC according to their genetic burden. In the locus on chromosome 17 the sequencing analysis revealed the presence of 203 SNPs associated with disease (best signal p= 1.11x10-23). We tested, based on their availability, the 203 SNPs for a cis-eQTL association using Braineac, Gtex Portal and SNPExpress databases. We found an association of several SNPs with the expression of EFCAB13 in brain tissues, while in more immunological tissues we observed that also TBKBP1 is regulated, with an opposite direction compared to brain. A total of 12 signals were identified by the sequencing analysis in the intergenic locus on chromosome 3. No eQTL associations were found for any of those SNPs and their function needs to be better explored. Concluding, we confirmed the loci on chromosomes 17 and 3 as highly associated also in the Italian population and we better characterised the origin of the signals using a next-generation sequencing approach. Moreover, we observed tissue-dependent regulatory functions, opening questions on the role of EFCAB13 and TBKBP1 in MS.
Identification and characterization of multiple sclerosis associated loci in the continental italian population
Anand S;Mangano E;Bordoni R;De Bellis G;
2016
Abstract
Multiple sclerosis (MS) is a complex disorder characterized by myelin damage and neurodegeneration. Until now 103 susceptibility genetic loci have been identified through genome-wide association studies (GWAS), however they involved samples from several different countries that could have a different genetic and environmental predisposition. The aim of the present project was to identify and characterise the most associated regions in the Italian population following a multi-step approach. We started from 2 cohorts of Italian continental MS patients and healthy controls (HC): ITAGWAS (750 MS, 1291 HC) with available imputed genome-wide genotypes and ITAiChip (977 MS, 986 HC) with genotyping data in 184 immune regions. To boost the statistical power of the study, the top associated signals of association (p< 0.005) in the two Italian cohorts were meta-analysed with an imputation-based meta-analysed cohort of 20,512 cases and 19,145 HC of European ancestry from USA. A total of 16 loci of association were identified (p< 5x10-7) and then tested for an association in a third Italian cohort (903 MS, 884 HC). This replication phase confirmed the association of two loci on chromosome 17 and chromosome 3, already known to be associated with the disease. To better characterize them we next sequenced them in an Italian cohort of 600 MS and 408 HC using a pooling approach and comparing high-risk MS patients and low-risk HC according to their genetic burden. In the locus on chromosome 17 the sequencing analysis revealed the presence of 203 SNPs associated with disease (best signal p= 1.11x10-23). We tested, based on their availability, the 203 SNPs for a cis-eQTL association using Braineac, Gtex Portal and SNPExpress databases. We found an association of several SNPs with the expression of EFCAB13 in brain tissues, while in more immunological tissues we observed that also TBKBP1 is regulated, with an opposite direction compared to brain. A total of 12 signals were identified by the sequencing analysis in the intergenic locus on chromosome 3. No eQTL associations were found for any of those SNPs and their function needs to be better explored. Concluding, we confirmed the loci on chromosomes 17 and 3 as highly associated also in the Italian population and we better characterised the origin of the signals using a next-generation sequencing approach. Moreover, we observed tissue-dependent regulatory functions, opening questions on the role of EFCAB13 and TBKBP1 in MS.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
