Genetic architecture of circulating lipid levels
Genetic architecture of circulating lipid levels
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DOI：
10.1038/ejhg.2011.21
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发表时间：
2011-07-01
影响因子：
5.2
通讯作者：
van Duijn, Cornelia M.
中科院分区：
文献类型：
--
作者：
Demirkan, Ayse;Amin, Najaf;van Duijn, Cornelia M.
低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、甘油三酯（TG）和总胆固醇（TC）的血清浓度是心血管疾病的重要遗传危险因素。尽管循环脂质水平的全基因组关联研究（GWAS）已经确定了许多位点，但这些性状的大部分遗传性仍然无法解释。通过将多个独立标记组合成加性遗传风险评分，可以检测无法解释的遗传变异的证据。这种多基因评分是利用 ENGAGE 联盟 GWAS 对血脂的结果构建的，用于预测鹿特丹研究 II (RS-II) 一项基于人群的独立研究中的血脂水平。我们还测试了不同脂质表型具有共同遗传基础的证据。最后，在通路分析之前使用多基因评分方法确定替代的全基因组显着性阈值，并将这些结果与基于经典全基因组显着性阈值的结果进行比较。我们的研究提供的证据表明，许多影响循环脂质水平的位点仍未被发现。交叉预测模型表明，确定 LDL-C、HDL-C 和 TG 水平所涉及的多基因背景之间存在少量重叠。与仅使用全基因组显着位点相比，利用 TC 的最佳多基因评分的通路分析发现了额外的信息。这些结果表明，循环脂质的遗传结构涉及许多未发现的、影响非常小的变异，并且增加 GWAS 样本量将能够识别调节脂质水平的新变异。欧洲人类遗传学杂志 (2011) 19, 813-819; doi：10.1038/ejhg.2011.21； 2011 年 3 月 30 日在线发布
Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels. European Journal of Human Genetics (2011) 19, 813-819; doi:10.1038/ejhg.2011.21; published online 30 March 2011