A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
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DOI：
10.1093/hmg/ddp059
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发表时间：
2009-04-15
影响因子：
3.5
通讯作者：
Traynor, Bryan J.
中科院分区：
文献类型：
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作者：
Chio, Adriano;Schymick, Jennifer C.;Traynor, Bryan J.
散发性肌萎缩性侧索硬化症（ALS）的病因在很大程度上是未知的，但遗传因素被认为在决定运动神经元变性的易感性方面起着重要作用。为了确定改变ALS风险的遗传变异，我们进行了一项两阶段的全基因组关联研究（GWAS）：我们在553名ALS患者和2338名对照中进行了545066个snp的初始GWAS，通过在三个独立的队列（包括2160例病例和3008名对照）中检测第一阶段的7600个最相关的snp。选择用于复制的snp均未超过Bonferroni阈值的显著性。两个最显著相关的SNPs rs2708909和rs2708851[比值比（OR）分别为1.17和1.18，p值分别为6.98 × 10（-7）和1.16 × 10(-6)]位于染色体7p13.3上包含SUNC1、HUS1和C7orf57基因的175 kb连锁不平衡区内。这些关联在原始队列中没有达到全基因组意义，在另外一个989例美国病例和327例对照的独立队列中也没有重复（OR = 1.18和1.19，p值分别= 0.08和0.06）。因此，我们选择谨慎地将我们的数据解释为需要额外确认的假设生成，特别是因为所有先前报道的ALS基因座都未能成功复制。事实上，在我们的研究中，在先前的散发性ALS的GWAS中发现的三个位点（FGGY， ITPR2和DPP6）与疾病没有显著相关性。我们的研究结果表明，ALS的遗传和临床异质性比以前认识到的要大。我们研究的基因型数据已在网上提供，以促进此类未来的努力。
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.