Gene ontology analysis of pairwise genetic associations in two genome-wide studies of sporadic ALS.
Gene ontology analysis of pairwise genetic associations in two genome-wide studies of sporadic ALS.
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DOI：
10.1186/1756-0381-5-9
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发表时间：
2012-07-28
期刊：
影响因子：
4.5
通讯作者：
Moore JH
中科院分区：
文献类型：
--
作者：
Kim NC;Andrews PC;Asselbergs FW;Frost HR;Williams SM;Harris BT;Read C;Askland KD;Moore JH
越来越清楚的是，人类常见疾病有一个复杂的遗传结构，其特点是既有相加的遗传效应，也有非相加的遗传效应。本研究的目的是确定加性和非加性遗传关联的模式是否聚集在基因本体论(GO)所定义的特定功能群中。我们首先使用多因素降维(MDR)方法估计了所有成对的可加性和非可加性遗传效应，该方法对潜在的遗传模型几乎没有假设。在ALS的两项全基因组相关性研究中，使用排列测试来评估统计学意义。检测数据包括276名ALS患者和271名健康对照，复制数据包括221名ALS患者和211名健康对照。这两项研究都包括大约550,000个单核苷酸多态(SNPs)的基因类型。如果每个SNP位于起始或结束的500 kb以内，则每个SNP被映射到一个基因。根据每个SNP与其他SNP的最强联合效应，为每个SNP分配一个p值。然后，我们使用探索性视觉分析方法和软件，根据基因中α = 水平上显著SNPs的过量为每个基因分配p值。我们还根据α = 水平上显著基因的过度丰度，使用EVA为每个GO组分配p值。在两项研究中，GO类别被确定为重复该类别是否在α = 0.05水平上显著。我们发现两个围棋类别在两项研究中都是相同的。第一个是细胞成分组织和生物发生的调节，这是一个GO生物学过程，在检测和复制研究中的p值分别为0.010和0.014。第二种是GO细胞成分肌动蛋白细胞骨架，在检测和复制研究中的p值分别为0.040和0.046。对散发性ALS的两个GWA的成对遗传关联的通径分析揭示了一组与细胞成分组织和肌动蛋白细胞骨架有关的基因，更具体地说，这些基因在以前的GWA中没有报道。然而，先前的生物学研究表明肌动蛋白细胞骨架与肌萎缩侧索硬化症和其他运动神经元疾病有关。这项研究支持这样一种观点，即对GWAS数据的通径水平分析可能会发现使用传统的一次一个SNP方法没有揭示的重要关联。
It is increasingly clear that common human diseases have a complex genetic architecture characterized by both additive and nonadditive genetic effects. The goal of the present study was to determine whether patterns of both additive and nonadditive genetic associations aggregate in specific functional groups as defined by the Gene Ontology (GO). We first estimated all pairwise additive and nonadditive genetic effects using the multifactor dimensionality reduction (MDR) method that makes few assumptions about the underlying genetic model. Statistical significance was evaluated using permutation testing in two genome-wide association studies of ALS. The detection data consisted of 276 subjects with ALS and 271 healthy controls while the replication data consisted of 221 subjects with ALS and 211 healthy controls. Both studies included genotypes from approximately 550,000 single-nucleotide polymorphisms (SNPs). Each SNP was mapped to a gene if it was within 500 kb of the start or end. Each SNP was assigned a p-value based on its strongest joint effect with the other SNPs. We then used the Exploratory Visual Analysis (EVA) method and software to assign a p-value to each gene based on the overabundance of significant SNPs at the α = 0.05 level in the gene. We also used EVA to assign p-values to each GO group based on the overabundance of significant genes at the α = 0.05 level. A GO category was determined to replicate if that category was significant at the α = 0.05 level in both studies. We found two GO categories that replicated in both studies. The first, ‘Regulation of Cellular Component Organization and Biogenesis’, a GO Biological Process, had p-values of 0.010 and 0.014 in the detection and replication studies, respectively. The second, ‘Actin Cytoskeleton’, a GO Cellular Component, had p-values of 0.040 and 0.046 in the detection and replication studies, respectively. Pathway analysis of pairwise genetic associations in two GWAS of sporadic ALS revealed a set of genes involved in cellular component organization and actin cytoskeleton, more specifically, that were not reported by prior GWAS. However, prior biological studies have implicated actin cytoskeleton in ALS and other motor neuron diseases. This study supports the idea that pathway-level analysis of GWAS data may discover important associations not revealed using conventional one-SNP-at-a-time approaches.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
离子通道和精神分裂症：一种基于基因集的 GWAS 数据分析方法，用于生物学假设检验。
影响因子：
5.3
作者：
Askland K;Read C;O'Connell C;Moore JH
通讯作者：
Moore JH
影响因子：
48
作者：
Laaksovirta, Hannu;Peuralinna, Terhi;Schymick, Jennifer C.;Scholz, Sonja W.;Lai, Shaoi-Lin;Myllykangas, Liisa;Sulkava, Raimo;Jansson, Lilja;Hernandez, Dena G.;Gibbs, J. Raphael;Nalls, Michael A.;Heckerman, David;Tienari, Pentti J.;Traynor, Bryan J.
通讯作者：
Traynor, Bryan J.
影响因子：
9.8
作者：
Wang, Kai;Li, Mingyao;Bucan, Maja
通讯作者：
Bucan, Maja
影响因子：
9.8
作者：
Ritchie, MD;Hahn, LW;Moore, JH
通讯作者：
Moore, JH