1. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
- Author
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Massimo Corbo, Cristina Cereda, Simon Cronin, Carl D. Langefeld, John Landers, Evadnie Rampersaud, Silvana Penco, Stefano Signorini, Jonathan D. Glass, Simon Topp, Gkazi Athina Soraya, Jan H. Veldink, Giancarlo Logroscino, Michael A van Es, Anne Birve, Karen E. Morrison, Davide Gentilini, Robert H. Brown, Paul W.J. van Vught, Jack W. Miller, Franco Taroni, Kreshnik B. Ahmeti, Stefania Corti, Barbara Castellotti, Aldo Quattrone, Senda Ajroud-Driss, Judith Melki, Philip Van Damme, Gabriele Siciliano, Vincent Meininger, Daniela Calini, Julie Williams, Cinzia Gellera, Anne Farmer, Valentina Moskvina, Antonia Ratti, Jonathan L. Haines, John Powell, Giacomo P. Comi, Scott Heller, Sandra D'Alfonso, Nailah Siddique, Margaret A. Pericak-Vance, Angela Marsili, Gabriele Mora, Stella Gagliardi, Peter M. Andersen, Giorgia Querin, Orla Hardiman, Anna Maria Di Blasio, Nicola Ticozzi, Maurizio Inghilleri, Francesco Saccà, Wu-Yen Hung, Cinzia Tiloca, J.G. Zheng, Letizia Mazzini, Mary C. Comeau, Michael E. Weale, James M. Jaworski, Jie Huang, Jennifer Armstrong, Filosto Massimo, Elena Pegoraro, Caroline Vance, Roberto Del Bo, Ewout J N Groen, Teepu Siddique, Nigel Leigh, Lucia Corrado, Josh D. Grab, Mauro Ceroni, Christopher Shaw, Massimiliano Filosto, Alessandra Ferlini, Vincenzo Silani, Adriano Chiò, Sandro Sorbi, Isabella Fogh, Giorgia Puorro, Wenjie Chen, Maria Rosaria Monsurrò, Alessandro Filla, Humaira Khan, Wim Robberecht, Cathryn M. Lewis, Ashley R. Jones, Pensato Viviana, Kuang Lin, Pamela J. Shaw, Ammar Al-Chalabi, Bryan J. Traynor, Leonard H. van den Berg, Michael Sendtner, Vincenzo Brescia Morra, Aleksey Shatunov, Frank P. Diekstra, Vincenzo La Bella, Gianni Sorarù, Robert L. Sufit, Daniel J. Overste, Yi Yang, Paolo Bongioanni, Miranda C. Marion, Bradley N. Smith, Francesca Luisa Conforti, Hylke M. Blauw, Lucie Bruijn, Isabella Laura Simone, Russell L. McLaughlin, Fogh, I., Ratti, A., Gellera, C., Lin, K., Tiloca, C., Moskvina, V., Corrado, L., Sorarù, G., Cereda, C., Corti, S., Gentilini, D., Calini, D., Castellotti, B., Mazzini, L., Querin, G., Gagliardi, S., Bo, R. D., Conforti, F. L., Siciliano, G., Inghilleri, M., Sacca', Francesco, Bongioanni, P., Penco, S., Corbo, M., Sorbi, S., Filosto, M., Ferlini, A., Di, A. M., Signorini, S., Shatunov, A., Jones, A., Shaw, P. J., Morrison, K. E., Farmer, A. E., Damme, P. V., Robberecht, W., Chiò, A., Traynor, B. J., Sendtner, M., Melki, J., Meininger, V., Hardiman, O., Andersen, P. M., Leigh, N. P., Glass, J. D., Overste, D., Diekstra, F. P., Veldink, J. H., Van, M. A., Shaw, C. E., Weale, M. E., Lewis, C. M., Williams, J., Brown, R. H., Landers, J. E., Ticozzi, N., Ceroni, M., Pegoraro, E., Comi, G. P., D'Alfonso, S., Van, L. H., Taroni, F., Al-Chalabi, A., Powell, J., Silani, V., S., T., S., Consortium, and Filla, Alessandro
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genetic structures ,Prognosi ,Single-nucleotide polymorphism ,Locus (genetics) ,Genome-wide association study ,Biology ,Chromosomes ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,Genetics ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,amyotrophic lateral sclerosis ,genetic ,0303 health sciences ,Amyotrophic Lateral Sclerosis ,Case-Control Studies ,Chromosomes, Human, Pair 17 ,Prognosis ,Genome-Wide Association Study ,Pair 17 ,Association Studies Articles ,Case-control study ,General Medicine ,Heritability ,medicine.disease ,3. Good health ,Case-Control Studie ,030217 neurology & neurosurgery ,Imputation (genetics) ,Amyotrophic Lateral Sclerosi ,Human - Abstract
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
- Published
- 2013
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