Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
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DOI：
10.1038/ng.442
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发表时间：
2009-10-01
期刊：
影响因子：
30.8
通讯作者：
van den Berg, Leonard H.
中科院分区：
文献类型：
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作者：
van Es, Michael A.;Veldink, Jan H.;van den Berg, Leonard H.
我们在2，323名散发性肌萎缩侧索硬化症（ALS）患者和9，013名对照受试者中进行了全基因组关联研究，并在第二个独立队列中评估了2，532名受影响者和5，940名对照的所有SNP，P < 1.0 x 10（-4）。全基因组数据分析显示，一种SNP rs 12608932具有全基因组显著性，P = 1.30 x 10（-9）。该SNP在第二队列中显示出稳健的复制（P = 1.86 x 10（-6）），并且两个阶段的组合分析产生P = 2.53 x 10（-14）。rs 12608932 SNP位于19p13.3，并映射到UNC 13 A边界内的单倍型块，其调节神经肌肉突触处的神经递质如谷氨酸的释放。在两个阶段的联合分析中，对其他SNP的随访显示了另外两个SNP（rs 2814707，P = 7.45 x 10（-9）和rs3849942，P = 1.01 x 10（-8））的全基因组显著性。这些SNPs位于染色体9p21.2，在家族性ALS与额颞叶痴呆的连锁区域，以前在几个大的家系中发现。
We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.