Imputation of Exome Sequence Variants into Population-Based Samples and Blood-Cell-Trait-Associated Loci in African Americans: NHLBI GO Exome Sequencing Project
Imputation of Exome Sequence Variants into Population-Based Samples and Blood-Cell-Trait-Associated Loci in African Americans: NHLBI GO Exome Sequencing Project
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DOI：
10.1016/j.ajhg.2012.08.031
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发表时间：
2012-11-02
影响因子：
9.8
通讯作者：
Li, Yun
中科院分区：
文献类型：
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作者：
Auer, Paul L.;Johnsen, Jill M.;Li, Yun
研究人员已经成功地应用外显子组测序在选定的家族性、高度渗透性疾病患者中发现了因果变异。我们论证了外显子组测序和归因在发现与复杂数量性状相关的低频变异方面的作用。我们在一个由761名非裔美国人组成的参考小组中进行了外显子组测序，然后将新发现的变异体输入超过13,000名非裔美国人的更大样本中，以进行与血细胞特征的关联测试，包括血红蛋白、红细胞压积、白细胞计数和血小板计数。首先，我们通过展示传统基因分型阵列没有涵盖的变异的全基因组显著相关性来说明我们方法的可行性；例如，其中一个这样的关联是较高的血小板计数与编码血小板生成素受体基因的P.Lys39Asn氨基酸替换的MPL c.117G>；T(p.Lys39Asn)变体之间的关联(p=1.5x10(-11))。其次，我们确定了LCT的错义变异与较高的白细胞计数之间的关联(p=4x10(-13))。第三，我们确定了可能导致几个已知血细胞相关基因座等位基因异质性的低频编码变异：MP1 c.754T>；C(p.Tyr252His)与较高的血小板计数相关；CD36 c.975T>；G(p.Tyr325*)与较低的血小板计数相关；以及α-珠蛋白基因座位上的几个错义变异与较低的血红蛋白相关。通过识别与以前未被全基因组关联研究报道的血细胞特征相关的低频错义变异，我们确立了外显子组测序随后的归属是在基于大规模人群的研究中解剖复杂的、遗传异质性特征的一种强有力的方法。
Researchers have successfully applied exome sequencing to discover causal variants in selected individuals with familial, highly penetrant disorders. We demonstrate the utility of exome sequencing followed by imputation for discovering low-frequency variants associated with complex quantitative traits. We performed exome sequencing in a reference panel of 761 African Americans and then imputed newly discovered variants into a larger sample of more than 13,000 African Americans for association testing with the blood cell traits hemoglobin, hematocrit, white blood count, and platelet count. First, we illustrate the feasibility of our approach by demonstrating genome-wide-significant associations for variants that are not covered by conventional genotyping arrays; for example, one such association is that between higher platelet count and an MPL c.117G>T (p.Lys39Asn) variant encoding a p.Lys39Asn amino acid substitution of the thrombpoietin receptor gene (p = 1.5 x 10(-11)). Second, we identified an association between missense variants of LCT and higher white blood count (p = 4 x 10(-13)). Third, we identified low-frequency coding variants that might account for allelic heterogeneity at several known blood cell-associated loci: MPL c.754T>C (p.Tyr252His) was associated with higher platelet count; CD36 c.975T>G (p.Tyr325*) was associated with lower platelet count; and several missense variants at the alpha-globin gene locus were associated with lower hemoglobin. By identifying low-frequency missense variants associated with blood cell traits not previously reported by genome-wide association studies, we establish that exome sequencing followed by imputation is a powerful approach to dissecting complex, genetically heterogeneous traits in large population-based studies.