A genome-wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study.
A genome-wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study.
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DOI：
10.1002/gepi.22042
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发表时间：
2017-05
影响因子：
2.1
通讯作者：
Palmer ND
中科院分区：
文献类型：
--
作者：
Gao C;Hsu FC;Dimitrov LM;Okut H;Chen YI;Taylor KD;Rotter JI;Langefeld CD;Bowden DW;Palmer ND
插入和缺失（INDEL）代表了人类基因组个体间变异的很大一部分，但它们对表型的贡献却知之甚少。为了确认推算 INDEL 的质量并研究其在介导心脏代谢表型中的作用，我们对 1024 名墨西哥裔美国人的 15 个表型、1,273,952 个推算 INDEL 进行了全基因组关联和连锁分析。使用全外显子组测序验证了插补质量，常见 INDEL 的平均 kappa 为 0.93（MAF≥5%）。关联分析揭示了胆固醇转移蛋白基因（CETP）与高密度脂蛋白水平的一个全基因组显着关联信号（rs36229491，P=3.06×10−12）；连锁分析确定了两个 LOD>5 的峰（rs60560566，胰岛素敏感性 (SI) 的 LOD=5.36 和 rs5825825，脂联素水平的 LOD=5.11）。观察到连锁和关联之间暗示性的重叠信号：包含 WSC 结构域 2 基因 (WSCD2) 中的 rs59849892 与 SI 相关且名义上连锁（P=1.17×10−7，LOD=1.99）。在人类胰岛细胞表达研究中，该基因与葡萄糖代谢有关。此外，rs201606363与低密度脂蛋白（P=4.73×10−4，LOD=3.67）、载脂蛋白B（P=1.39×10−3，LOD=4.64）和总胆固醇（P=1.35×10−2，LOD=3.80）水平相关。 rs201606363是UBE2F-SCLY融合基因的内含子变体，可能通过硒代谢调节胆固醇。总之，这些结果证实了从基于芯片的 SNP 基因型推算 INDEL 的可行性。使用关联和连锁对这些变异进行分析，复制了先前识别的 SNP 信号，并识别了多个新的 INDEL 信号。这些结果支持将 INDEL 纳入遗传研究中，以更全面地探究遗传变异谱。
Insertions and deletions (INDELs) represent a significant fraction of inter-individual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (MAF≥5%). Association analysis revealed one genome-wide significant association signal for the Cholesterylester Transfer Protein gene (CETP) with high density lipoprotein levels (rs36229491, P=3.06×10−12); linkage analysis identified two peaks with LOD>5 (rs60560566, LOD=5.36 with insulin sensitivity (SI) and rs5825825, LOD=5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC Domain Containing 2 gene (WSCD2) was associated and nominally linked with SI (P=1.17×10−7, LOD=1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low density lipoprotein (P=4.73×10−4, LOD=3.67), apolipoprotein B (P=1.39×10−3, LOD=4.64), and total cholesterol (P=1.35×10−2, LOD=3.80) levels. rs201606363 is an intronic variant of the UBE2F-SCLY fusion gene which may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array-based SNP genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These results support the inclusion of INDELs into genetic studies to more fully interrogate the spectrum of genetic variation.