Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis
Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis
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DOI：
10.1016/j.ajhg.2012.08.021
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发表时间：
2012-10-05
影响因子：
9.8
通讯作者：
Morris, Andrew P.
中科院分区：
文献类型：
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作者：
Franceschini, Nora;van Rooij, Frank J. A.;Morris, Andrew P.
许多疾病与血清蛋白浓度改变有关，包括营养不良、癌症、心血管、肾脏和炎症疾病。尽管这些蛋白质浓度具有高度遗传性，但对其潜在的遗传决定因素知之甚少。通过对欧洲血统和日本全基因组关联研究的跨种族荟萃分析，我们确定了血清白蛋白（HPN-SCN1B、GCKR-FNDC4、SERPINF2-WDR81、TNFRSF11A-ZCCHC2、FRMDS-WDR76 和 RPS11-FCGRT）具有全基因组显着性（p < 5 x 10(-8)）的六个位点，最多可达53,190 名欧洲血统个体和 9,380 名日本个体）和三个总蛋白位点（TNFRS13B、6q21.3 和 ELL2，最多 25,539 名欧洲血统个体和 10,168 名日本个体）。我们几乎没有观察到欧洲和日本血统群体之间这些位点等位基因效应异质性的证据，但通过利用连锁不平衡分布的跨种族差异，在潜在因果变异的精细定位分辨率方面获得了实质性改进。我们证明了最密切相关的血清白蛋白位点 HPN 的功能作用，Hpn 敲除小鼠表现出低血浆白蛋白浓度。其他与血清白蛋白相关的基因座包含与核糖体功能、蛋白质翻译和蛋白酶体降解相关的基因，而与血清总蛋白相关的基因座包括与免疫功能相关的基因。我们的结果强调了跨种族荟萃分析在复杂性状位点的发现和精细定位方面的优势，并为血清蛋白浓度的潜在遗传结构及其与人类疾病的关联提供了初步见解。
Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 x 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMDS-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.