Fogh Isabella, Ratti Antonia, Gellera Cinzia, Lin Kuang, Tiloca Cinzia, Moskvina Valentina, Corrado Lucia, Sorarù Gianni, Cereda Cristina, Corti Stefania, Gentilini Davide, Calini Daniela, Castellotti Barbara, Mazzini Letizia, Querin Giorgia, Gagliardi Stella, Del Bo Roberto, Conforti Francesca L, Siciliano Gabriele, Inghilleri Maurizio, Saccà Francesco, Bongioanni Paolo, Penco Silvana, Corbo Massimo, Sorbi Sandro, Filosto Massimiliano, Ferlini Alessandra, Di Blasio Anna M, Signorini Stefano, Shatunov Aleksey, Jones Ashley, Shaw Pamela J, Morrison Karen E, Farmer Anne E, Van Damme Philip, Robberecht Wim, Chiò Adriano, Traynor Bryan J, Sendtner Michael, Melki Judith, Meininger Vincent, Hardiman Orla, Andersen Peter M, Leigh Nigel P, Glass Jonathan D, Overste Daniel, Diekstra Frank P, Veldink Jan H, van Es Michael A, Shaw Christopher E, Weale Michael E, Lewis Cathryn M, Williams Julie, Brown Robert H, Landers John E, Ticozzi Nicola, Ceroni Mauro, Pegoraro Elena, Comi Giacomo P, D'Alfonso Sandra, van den Berg Leonard H, Taroni Franco, Al-Chalabi Ammar, Powell John, Silani Vincenzo
Department of Neuroscience.
Hum Mol Genet. 2014 Apr 15;23(8):2220-31. doi: 10.1093/hmg/ddt587. Epub 2013 Nov 20.
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.
对肌萎缩侧索硬化症（ALS）家族性位点突变的鉴定，为这种快速进展的致命性神经退行性疾病的病因学提供了新的见解。然而，除了在9p21.2处的复制位点外，针对更常见的（约90%）散发性ALS形式的全基因组关联研究（GWAS）成效较差。为了确定与疾病易感性相关的新位点，我们开展了迄今为止最大规模的ALS关联研究，并进行了一项GWAS荟萃分析研究，将由SLAGEN（意大利ALS遗传学联盟）收集的3959名新基因分型的意大利个体（1982例病例和1977例对照）与由ALSGEN（国际ALS遗传学联盟）收集的来自荷兰、美国、英国、瑞典、比利时、法国、爱尔兰和意大利的样本相结合。我们对总共13225名个体进行了分析，其中6100例病例和7125例对照，检测了近700万个单核苷酸多态性（SNP）。我们在17q11.2处确定了一个具有全基因组显著性的新位点（rs34517613，P = 1.11×10⁻⁸；优势比0.82），当与来自一个包含4656名个体的复制队列的基因型数据合并时得到了验证（P = 8.62×10⁻⁹；优势比0.833）。此外，我们证实了先前报道的9p21.2处的关联（rs3849943，P = 7.69×10⁻⁹；优势比1.16）。最后，我们使用考虑了所有SNP的线性混合模型估计，常见变异对散发性ALS遗传力的贡献约为12%。我们的结果为散发性ALS的遗传结构提供了见解，证实了常见变异会导致发病风险，并且有足够效力的研究能够识别出新的易感位点。
