Genetic and Genomic Epidemiology Unit, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
PLoS One. 2011;6(7):e22070. doi: 10.1371/journal.pone.0022070. Epub 2011 Jul 15.
The integrated analysis of genotypic and expression data for association with complex traits could identify novel genetic pathways involved in complex traits. We profiled 19,573 expression probes in Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from 299 twins and correlated these with 44 quantitative traits (QTs). For 939 expressed probes correlating with more than one QT, we investigated the presence of eQTL associations in three datasets of 57 CEU HapMap founders and 86 unrelated twins. Genome-wide association analysis of these probes with 2.2 m SNPs revealed 131 potential eQTLs (1,989 eQTL SNPs) overlapping between the HapMap datasets, five of which were in cis (58 eQTL SNPs). We then tested 535 SNPs tagging the eQTL SNPs, for association with the relevant QT in 2,905 twins. We identified nine potential SNP-QT associations (P<0.01) but none significantly replicated in five large consortia of 1,097-16,129 subjects. We also failed to replicate previous reported eQTL associations with body mass index, plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides levels derived from lymphocytes, adipose and liver tissue. Our results and additional power calculations suggest that proponents may have been overoptimistic in the power of LCLs in eQTL approaches to elucidate regulatory genetic effects on complex traits using the small datasets generated to date. Nevertheless, larger tissue-specific expression data sets relevant to specific traits are becoming available, and should enable the adoption of similar integrated analyses in the near future.
综合分析基因型和表达数据与复杂性状的关联可以确定与复杂性状相关的新的遗传途径。我们对 299 对双胞胎的 Epstein-Barr 病毒转化的淋巴母细胞系 (LCL) 中的 19573 个表达探针进行了分析，并将这些探针与 44 个定量性状 (QT) 相关联。对于与多个 QT 相关的 939 个表达探针，我们在 57 个 CEU HapMap 创始人和 86 个无关双胞胎的三个数据集调查了 eQTL 关联的存在。对这些探针与 2200 万个 SNPs 的全基因组关联分析显示，在 HapMap 数据集中有 131 个潜在的 eQTL(1989 个 eQTL SNPs)重叠，其中 5 个是顺式的 (58 个 eQTL SNPs)。然后，我们在 2905 对双胞胎中测试了 535 个标记 eQTL SNPs 的 SNP 与相关 QT 的关联。我们确定了 9 个潜在的 SNP-QT 关联 (P<0.01)，但在五个包含 1097-16129 名受试者的大型联盟中，没有一个显著复制。我们也未能复制先前报道的与体重指数、血浆低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯水平相关的 eQTL 关联，这些结果来自淋巴细胞、脂肪组织和肝脏组织。我们的结果和额外的功效计算表明，使用迄今为止生成的小型数据集，LCL 在 eQTL 方法中阐明复杂性状的调节遗传效应的功效，倡导者可能过于乐观。尽管如此，与特定性状相关的更大的组织特异性表达数据集正在变得可用，并且应该能够在不久的将来采用类似的综合分析。
