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


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.

SUBMITTER: Fogh I 

PROVIDER: S-EPMC3959809 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Fogh Isabella I   Ratti Antonia A   Gellera Cinzia C   Lin Kuang K   Tiloca Cinzia C   Moskvina Valentina V   Corrado Lucia L   Sorarù Gianni G   Cereda Cristina C   Corti Stefania S   Gentilini Davide D   Calini Daniela D   Castellotti Barbara B   Mazzini Letizia L   Querin Giorgia G   Gagliardi Stella S   Del Bo Roberto R   Conforti Francesca L FL   Siciliano Gabriele G   Inghilleri Maurizio M   Saccà Francesco F   Bongioanni Paolo P   Penco Silvana S   Corbo Massimo M   Sorbi Sandro S   Filosto Massimiliano M   Ferlini Alessandra A   Di Blasio Anna M AM   Signorini Stefano S   Shatunov Aleksey A   Jones Ashley A   Shaw Pamela J PJ   Morrison Karen E KE   Farmer Anne E AE   Van Damme Philip P   Robberecht Wim W   Chiò Adriano A   Traynor Bryan J BJ   Sendtner Michael M   Melki Judith J   Meininger Vincent V   Hardiman Orla O   Andersen Peter M PM   Leigh Nigel P NP   Glass Jonathan D JD   Overste Daniel D   Diekstra Frank P FP   Veldink Jan H JH   van Es Michael A MA   Shaw Christopher E CE   Weale Michael E ME   Lewis Cathryn M CM   Williams Julie J   Brown Robert H RH   Landers John E JE   Ticozzi Nicola N   Ceroni Mauro M   Pegoraro Elena E   Comi Giacomo P GP   D'Alfonso Sandra S   van den Berg Leonard H LH   Taroni Franco F   Al-Chalabi Ammar A   Powell John J   Silani Vincenzo V  

Human molecular genetics 20131120 8


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 undertake  ...[more]

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