Gene and pathway-based second-wave analysis of genome-wide association studies
Gene and pathway-based second-wave analysis of genome-wide association studies
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DOI：
10.1038/ejhg.2009.115
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发表时间：
2010-01-01
影响因子：
5.2
通讯作者：
Xiong, Momiao
中科院分区：
文献类型：
--
作者：
Peng, Gang;Luo, Li;Xiong, Momiao
尽管全基因组关联研究（GWAS）在识别与复杂疾病相关的常见遗传变异方面取得了巨大成功，但目前的GWAS主要集中在单核苷酸多态性（SNP）分析上。然而，单SNP分析通常只能识别出少数最显著的SNP，这些SNP仅占遗传变异的一小部分，并且对复杂疾病的理解有限。为了克服这些局限性，我们提出基于基因和通路的关联分析作为GWAS的一种新范式。作为概念验证，我们对13项已发表的GWAS进行了全面的基于基因和通路的关联分析。我们的结果表明，所提出的GWAS新范式不仅识别出了包含单SNP分析所发现的显著SNP的基因，还检测到了一些新基因，其中每个单SNP所带来的疾病风险较小，但它们的联合作用与疾病的发展有关。结果还表明，GWAS的新范式能够识别出与疾病相关的具有生物学意义的通路，这通过使用基因表达数据进行的富集基因集分析得到了证实。《欧洲人类遗传学杂志》（2010年）18卷，111 - 117页；doi:10.1038/ejhg.2009.115；2009年7月8日在线发表
Despite the great success of genome-wide association studies (GWAS) in identification of the common genetic variants associated with complex diseases, the current GWAS have focused on single-SNP analysis. However, single-SNP analysis often identifies only a few of the most significant SNPs that account for a small proportion of the genetic variants and offers only a limited understanding of complex diseases. To overcome these limitations, we propose gene and pathway-based association analysis as a new paradigm for GWAS. As a proof of concept, we performed a comprehensive gene and pathway-based association analysis of 13 published GWAS. Our results showed that the proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single-SNP analysis, but also detected new genes in which each single SNP conferred a small disease risk; however, their joint actions were implicated in the development of diseases. The results also showed that the new paradigm for GWAS was able to identify biologically meaningful pathways associated with the diseases, which were confirmed by a gene-set-rich analysis using gene expression data. European Journal of Human Genetics (2010) 18, 111-117; doi:10.1038/ejhg.2009.115; published online 8 July 2009