A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts
A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts
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DOI：
10.1371/journal.pone.0173997
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发表时间：
2017-03-16
期刊：
影响因子：
3.7
通讯作者：
Kraft, Peter
中科院分区：
文献类型：
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作者：
Lindstrom, Sara;Loomis, Stephanie;Kraft, Peter
护士健康研究（NHS），护士健康研究II（NHSII），卫生专业人员随访研究（HPFS）和医生健康研究（PHS）收集了过去35年中约310，000名研究参与者的多重暴露和特征的详细纵向数据。队列中超过160，000名研究参与者捐赠了DNA样本，迄今为止，作为十二个主要结果的全基因组关联研究（GWAS）的一部分，已对20，691名受试者进行了基因分型。然而，这些研究使用了六种不同的GWAS阵列，使得难以进行次级表型分析或在研究中共享对照。为了允许对这些数据进行二次分析，我们创建了三个新的数据集，按平台系列合并，并使用通用参考面板（1，000个基因组I期版本）进行插补。在这里，我们描述了数据合并和插补背后的方法，并介绍了插补质量统计和两个GWAS的次要表型（体重指数（BMI）和静脉血栓栓塞（VTE））的关联结果。我们观察到FTO SNP rs 55872725的BMI关联最强（β = 0.45，p = 3.48x10（-22）），并且使用p = 0.05的显著性水平，我们复制了32个已知BMI SNP中的19个。对于VTE，我们观察到位于F5下游的rs 2040445 SNP（OR = 2.17，95% CI：1.79.2.63，p = 2.70x10（-15））的相关性最强，并且还观察到已知ABO和F11区域的显著相关性。这种汇集的资源可用于最大限度地提高跨队列收集的表型的GWAS的功效，并用于研究基因-环境相互作用以及罕见表型和基因型。
The Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)). We observed the strongest BMI association for the FTO SNP rs55872725 (beta = 0.45, p = 3.48x10(-22)), and using a significance level of p = 0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR = 2.17, 95% CI: 1.79.2.63, p = 2.70x10(-15)), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.