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

Isabella Fogh, Antonia Ratti, Cinzia Gellera, Kuang Lin, Cinzia Tiloca, Valentina Moskvina, Lucia Corrado, Gianni Sorarù, Cristina Cereda, Stefania Corti, Davide Gentilini, Daniela Calini, Barbara Castellotti, Letizia Mazzini, Giorgia Querin, Stella Gagliardi, Roberto Del bo, Francesca L. Conforti, Gabriele Siciliano, Maurizio InghilleriFrancesco Saccà, Paolo Bongioanni, Silvana Penco, Massimo Corbo, Sandro Sorbi, Massimiliano Filosto, Alessandra Ferlini, Anna M. Di blasio, Stefano Signorini, Aleksey Shatunov, Ashley Jones, Pamela J. Shaw, Karen E. Morrison, Anne E. Farmer, Philip Van damme, Wim Robberecht, Adriano Chiò, Bryan J. Traynor, Michael Sendtner, Judith Melki, Vincent Meininger, Orla Hardiman, Peter M. Andersen, Nigel P. Leigh, Jonathan D. Glass, Daniel Overste, Frank P. Diekstra, Jan H. Veldink, Michael A. Van es, Christopher E. Shaw, Michael E. Weale, Cathryn M. Lewis, Julie Williams, Robert H. Brown, John E. Landers, Nicola Ticozzi, Mauro Ceroni, Elena Pegoraro, Giacomo P. Comi, Sandra D'alfonso, Leonard H. Van den berg, Franco Taroni, Ammar Al-chalabi, John Powell, Vincenzo Silani

Research output: Contribution to journalArticle

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
Article numberddt587
Pages (from-to)2220-2231
Number of pages12
JournalHuman Molecular Genetics
Volume23
Issue number8
DOIs
Publication statusPublished - Apr 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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