Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, München, Germany.
Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
PLoS One. 2014 Apr 16;9(4):e93844. doi: 10.1371/journal.pone.0093844. eCollection 2014.
We aimed to assess whether whole blood expression quantitative trait loci (eQTLs) with effects in cis and trans are robust and can be used to identify regulatory pathways affecting disease susceptibility.
We performed whole-genome eQTL analyses in 890 participants of the KORA F4 study and in two independent replication samples (SHIP-TREND, N = 976 and EGCUT, N = 842) using linear regression models and Bonferroni correction.
In the KORA F4 study, 4,116 cis-eQTLs (defined as SNP-probe pairs where the SNP is located within a 500 kb window around the transcription unit) and 94 trans-eQTLs reached genome-wide significance and overall 91% (92% of cis-, 84% of trans-eQTLs) were confirmed in at least one of the two replication studies. Different study designs including distinct laboratory reagents (PAXgene™ vs. Tempus™ tubes) did not affect reproducibility (separate overall replication overlap: 78% and 82%). Immune response pathways were enriched in cis- and trans-eQTLs and significant cis-eQTLs were partly coexistent in other tissues (cross-tissue similarity 40-70%). Furthermore, four chromosomal regions displayed simultaneous impact on multiple gene expression levels in trans, and 746 eQTL-SNPs have been previously reported to have clinical relevance. We demonstrated cross-associations between eQTL-SNPs, gene expression levels in trans, and clinical phenotypes as well as a link between eQTLs and human metabolic traits via modification of gene regulation in cis.
Our data suggest that whole blood is a robust tissue for eQTL analysis and may be used both for biomarker studies and to enhance our understanding of molecular mechanisms underlying gene-disease associations.
我们旨在评估顺式和反式作用的全血表达数量性状基因座（eQTL）是否稳健，并且可以用于鉴定影响疾病易感性的调节途径。
我们使用线性回归模型和 Bonferroni 校正，在 KORA F4 研究的 890 名参与者和两个独立的复制样本（SHIP-TREND，N=976 和 EGCUT，N=842）中进行了全基因组 eQTL 分析。
在 KORA F4 研究中，4116 个顺式-eQTL（定义为 SNP 探针对，其中 SNP 位于转录单元的 500 kb 窗口内）和 94 个反式-eQTL 达到了全基因组显著水平，总体而言，至少有两个复制研究中的一个证实了 91%（92%的顺式-eQTL，84%的反式-eQTL）。不同的研究设计，包括不同的实验室试剂（PAXgene™与 Tempus™管），并不影响可重复性（单独的总体复制重叠率：78%和 82%）。免疫反应途径在顺式和反式-eQTL 中富集，并且显著的顺式-eQTL 在其他组织中部分共存（跨组织相似性为 40-70%）。此外，四个染色体区域在反式中同时对多个基因表达水平产生影响，并且 746 个 eQTL-SNP 先前已被报道与临床相关。我们证明了 eQTL-SNP、反式基因表达水平与临床表型之间的交叉关联，以及 eQTL 与人类代谢特征之间的联系，这是通过顺式基因调控的修饰实现的。
我们的数据表明，全血是 eQTL 分析的稳健组织，可同时用于生物标志物研究和增强我们对基因-疾病关联分子机制的理解。
