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

Fogh, I., Ratti, A., Gellera, C., Lin, K., Tiloca, C., Escott-Price, Valentina ORCID:, Corrado, L., Soraru, G., Cereda, C., Corti, S., Gentilini, D., Calini, D., Castellotti, B., Mazzini, L., Querin, G., Gagliardi, S., Del Bo, R., Conforti, F. L., Siciliano, G., Inghilleri, M., Sacca, F., Bongioanni, P., Penco, S., Corbo, M., Sorbi, S., Filosto, M., Ferlini, A., Di Blasio, A. M., Signorini, S., Shatunov, A., Jones, A., Shaw, P. J., Morrison, K. E., Farmer, A. E., Van Damme, P., Robberecht, W., Chio, 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 Es, M. A., Shaw, C. E., Weale, M. E., Lewis, C. M., Williams, J. ORCID:, Brown, R. H., Landers, J. E., Ticozzi, N., Ceroni, M., Pegoraro, E., Comi, G. P., D'Alfonso, S., van den Berg, L. H., Taroni, F., Al-Chalabi, A., Powell, J., Silani, V., Brescia Morra, V., Filla, A., Massimo, F., Marsili, A., Viviana, P., Puorro, G., La Bella, V., Logroscino, G., Monsurro, M. R., Quattrone, A., Simone, I. L., Ahmeti, K. B., Ajroud-Driss, S., Armstrong, J., Birve, A., Blauw, H. M., Bruijn, L., Chen, W., Comeau, M. C., Cronin, S., Soraya, G. A., Grab, J. D., Groen, E. J., Haines, J. L., Heller, S., Huang, J., Hung, W.-Y., ITALSGEN Consortium, Jaworski, J. M., Khan, H., Langefeld, C. D., Marion, M. C., McLaughlin, R. L., Miller, J. W., Mora, G., Pericak-Vance, M. A., Rampersaud, E., Siddique, N., Siddique, T., Smith, B. N., Sufit, R., Topp, S., Vance, C., van Vught, P., Yang, Y., Zheng, J. G. and Williams, Julie ORCID: 2014. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Human Molecular Genetics 23 (8) , pp. 2220-2231. 10.1093/hmg/ddt587

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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 3,959 newly genotyped Italian individuals (1,982 cases, 1,977 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 analyzed a total of 13,225 individuals, 6,100 cases and 7,125 controls for almost 7 million single nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 P=1.11 x 10−8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P=8.62 x 10−9; OR 0.833) of 4,656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P=7.69 x 10−9; OR 1.16). Finally, we have 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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Oxford University Press
ISSN: 0964-6906
Last Modified: 28 Oct 2022 09:56

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