Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
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DOI：
10.1073/pnas.0903103106
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发表时间：
2009-06-09
影响因子：
11.1
通讯作者：
Manolio, Teri A.
中科院分区：
文献类型：
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作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
我们已经从已发表的全基因组关联研究中开发了一个SNP-性状关联的在线目录，用于调查性状/疾病相关SNP（塔斯）的基因组特征。报告的塔斯很常见[中位风险等位基因频率36%，四分位距（IQR）21% - 53%]，并且与中等效应量相关[中位比值比（OR）1.33，IQR 1.20 - 1.61]。在20个基因组注释集中，与从基因分型阵列中随机选择的SNP相比，报告的塔斯仅在非同义位点[ OR = 3.9（2.2 - 7.0），p = 3.5 x 10（-7）]和5 kb启动子区域[ OR = 2.3（1.5 - 3.6），p = 3 x 10（-4）]中显著过高。虽然88%的塔斯是内含子（45%）或基因间（43%），但塔斯在内含子中并不多见，在基因间区域显著缺失[ OR = 0.44（0.34 = 0.58），p = 2.0 x 10（-9）]。在正选择区域中，预计仅会出现比预期偶然出现的TAS略多的塔斯[OR = 1.3（0.8 x 2.1），p = 0.2]。这个新的在线资源，以及对性状/疾病相关基因座的潜在功能的生物信息学预测，非常适合指导未来对复杂疾病病因中常见变异的作用的研究。
We have developed an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). Reported TASs were common [ median risk allele frequency 36%, interquartile range (IQR) 21% - 53%] and were associated with modest effect sizes [ median odds ratio ( OR) 1.33, IQR 1.20 - 1.61]. Among 20 genomic annotation sets, reported TASs were significantly overrepresented only in nonsynonymous sites [ OR = 3.9 (2.2 - 7.0), p = 3.5 x 10(-7)] and 5kb-promoter regions [ OR = 2.3 (1.5 - 3.6), p = 3 x 10(-4)] compared to SNPs randomly selected from genotyping arrays. Although 88% of TASs were intronic (45%) or intergenic (43%), TASs were not overrepresented in introns and were significantly depleted in intergenic regions [ OR = 0.44 (0.34 = 0.58), p = 2.0 x 10(-9)]. Only slightly more TASs than expected by chance were predicted to be in regions under positive selection [OR = 1.3 (0.8 x 2.1), p = 0.2]. This new online resource, together with bioinformatic predictions of the underlying functionality at trait/disease-associated loci, is well-suited to guide future investigations of the role of common variants in complex disease etiology.