A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

I. Fogh, A. Ratti, C. Gellera, K. Lin, C. Tiloca, V. Moskvina, L. Corrado, G. Soraru, C. Cereda, S. Corti, D. Gentilini, D. Calini, B. Castellotti, L. Mazzini, G. Querin, S. Gagliardi, R. Del Bo, F.L. Conforti, G. Siciliano, M. InghilleriF. Sacca, P. Bongioanni, S. Penco, M. Corbo, S. Sorbi, M. Filosto, A. Ferlini, A.M. Di Blasio, S. Signorini, A. Shatunov, A. Jones, P.J. Shaw, Karen E. Morrison, A.E. Farmer, P. Van Damme, W. Robberecht, A. Chio, B.J. Traynor, M. Sendtner, J. Melki, V. Meininger, O. Hardiman, P. M. Andersen, N. P. Leigh, J. D. Glass, D. Overste, F. P. Diekstra, J. H. Veldink, M. A. van Es, C. E. Shaw, M. E. Weale, Cathryn M. Lewis, Julie Williams, Robert H. Brown, J. E. Landers, N. Ticozzi, M. Ceroni, E. Pegoraro, G. P. Comi, S. D'Alfonso, L. H. van den Berg, F. Taroni, A. Al-Chalabi, J. Powell, V. Silani, V. Brescia Morra, A. Filla, F. Massimo, A. Marsili, P. Viviana, G. Puorro, V. La Bella, G. Logroscino, M. R. Monsurro, A. Quattrone, I. L. Simone, K. B. Ahmeti, S. Ajroud-Driss, Jennifer Armstrong, A. Birve, H. M. Blauw, L. Bruijn, Weinje Chen, M. C. Comeau, S. Cronin, G. A. Soraya, J. D. Grab, E. J. Groen, J. L. Haines, S. Heller, Jie Huang, W.-Y. Hung, H. Khan, James M. Jaworski, C. D. Langefeld, M. C. Marion, Russell L. McLaughlin, Jack W. Miller, G. Mora, M. A. Pericak-Vance, E. Rampersaud, N. Siddique, T. Siddique, Bradley N. Smith, R. Sufit, S. Topp, C. Vance, P. van Vught, Yi Yang, J. G. Zheng

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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.
Original languageEnglish
Pages (from-to)2220-2231
JournalHuman Molecular Genetics
Volume23
Issue number8
Early online date20 Nov 2013
DOIs
Publication statusPublished - 15 Apr 2014
Externally publishedYes

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