Contributions
Abstract: P1068
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Introduction: Multiple sclerosis (MS) is a complex disorder in which genetic factors play an important role together with non-genetic and environmental influences. Thanks to international efforts, more than 200 susceptibility genetic loci have been identified; however, given the nature of those studies, they involved samples from several countries, with possible underlying different genetic predisposition masking population-specific signals of association.
Aim: To characterise the most associated loci in the Continental Italian population.
Methods: We performed a genomic association study in 2 cohorts of Italian Continental MS patients and healthy controls (HC) (1727 MS, 2258 HC) for which genotypes imputed at genome-wide level or enriched in immune regions were available. To boost the statistical power of the study, we meta-analysed the top associated signals (p< 0.005) with an American meta-analysed cohort (~20,000 MS, ~20,000 HC) of European ancestry. Top signals (p< 5x10-7) were tested in a third Italian cohort (903 MS, 884 HC). Pool-based target sequencing of the loci was then performed (588 MS, 408 HC), followed by conditional cis eQTL analyses in 338 whole blood samples and in 6 brain tissues (average samples = 89) collected within the GTEx Project (v6p version).
Results: Discovery genomic association analysis led to the identification of 16 loci of association; 2 of them were confirmed in the replication dataset: one on chromosome 17 (~500kb) and one intergenic on chromosome 3 (~10kb). Target sequencing of the two loci identified 203 and 12 SNPs associated with the disease on chromosome 17 and chromosome 3, respectively. To further explore the putative functional role of the locus on chromosome 17, we next performed conditional cis eQTL finding that, among all the tested SNP, rs4267364 was the only variant identified through the discovery and replication phases that showed an eQTL association in whole blood with TBKBP1, an adaptor protein involved in the TNF/NFKB pathway (p=1.71x10-23). According to Roadmap Epigenomics and ENCODE projects, this SNP is localized in a genomic region with a putative enhancer role.
Conclusions: We confirmed a strong association of the locus on chromosome 17 with MS in continental Italian patients and prioritized the associated variants according to their regulatory effect. A target differential methylation analysis is ongoing to evaluate additional epigenetic effects and to prioritize causative relationships.
Disclosure: M. Sorosina, N. Barizzone, F. Clarelli, S. Anand, S. Lupoli, E. Mangano, R. Bordoni, M. Leone, D. Cusi, S. Bonfiglio, J.M. Garcia Manteiga, G. Tonon, G. De Bellis, P. De Jager, S. D'Alfonso: nothing to disclose
V. Martinelli: received honoraria from Biogen-Idec, Merck, Bayer, TEVA, Novartis and Genzyme
G. Comi has received compensation for consulting services and/or speaking activities with Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma.
N. Patsopoulos: received honoraria from Genentech and consulted for Merck
F. Esposito received honoraria from Almirall and Genzyme
F. Martinelli Boneschi received honoraria for consulting, research grant and travel expenses from TEVA neuroscience, Biogen IDEC, Merck Serono, Roche and Sanofi-Genzyme
Abstract: P1068
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Introduction: Multiple sclerosis (MS) is a complex disorder in which genetic factors play an important role together with non-genetic and environmental influences. Thanks to international efforts, more than 200 susceptibility genetic loci have been identified; however, given the nature of those studies, they involved samples from several countries, with possible underlying different genetic predisposition masking population-specific signals of association.
Aim: To characterise the most associated loci in the Continental Italian population.
Methods: We performed a genomic association study in 2 cohorts of Italian Continental MS patients and healthy controls (HC) (1727 MS, 2258 HC) for which genotypes imputed at genome-wide level or enriched in immune regions were available. To boost the statistical power of the study, we meta-analysed the top associated signals (p< 0.005) with an American meta-analysed cohort (~20,000 MS, ~20,000 HC) of European ancestry. Top signals (p< 5x10-7) were tested in a third Italian cohort (903 MS, 884 HC). Pool-based target sequencing of the loci was then performed (588 MS, 408 HC), followed by conditional cis eQTL analyses in 338 whole blood samples and in 6 brain tissues (average samples = 89) collected within the GTEx Project (v6p version).
Results: Discovery genomic association analysis led to the identification of 16 loci of association; 2 of them were confirmed in the replication dataset: one on chromosome 17 (~500kb) and one intergenic on chromosome 3 (~10kb). Target sequencing of the two loci identified 203 and 12 SNPs associated with the disease on chromosome 17 and chromosome 3, respectively. To further explore the putative functional role of the locus on chromosome 17, we next performed conditional cis eQTL finding that, among all the tested SNP, rs4267364 was the only variant identified through the discovery and replication phases that showed an eQTL association in whole blood with TBKBP1, an adaptor protein involved in the TNF/NFKB pathway (p=1.71x10-23). According to Roadmap Epigenomics and ENCODE projects, this SNP is localized in a genomic region with a putative enhancer role.
Conclusions: We confirmed a strong association of the locus on chromosome 17 with MS in continental Italian patients and prioritized the associated variants according to their regulatory effect. A target differential methylation analysis is ongoing to evaluate additional epigenetic effects and to prioritize causative relationships.
Disclosure: M. Sorosina, N. Barizzone, F. Clarelli, S. Anand, S. Lupoli, E. Mangano, R. Bordoni, M. Leone, D. Cusi, S. Bonfiglio, J.M. Garcia Manteiga, G. Tonon, G. De Bellis, P. De Jager, S. D'Alfonso: nothing to disclose
V. Martinelli: received honoraria from Biogen-Idec, Merck, Bayer, TEVA, Novartis and Genzyme
G. Comi has received compensation for consulting services and/or speaking activities with Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma.
N. Patsopoulos: received honoraria from Genentech and consulted for Merck
F. Esposito received honoraria from Almirall and Genzyme
F. Martinelli Boneschi received honoraria for consulting, research grant and travel expenses from TEVA neuroscience, Biogen IDEC, Merck Serono, Roche and Sanofi-Genzyme