Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.
LIFE Research Center for Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.
PLoS One. 2022 May 23;17(5):e0268815. doi: 10.1371/journal.pone.0268815. eCollection 2022.
Although gene-expression (GE) and protein levels are typically strongly genetically regulated, their correlation is known to be low. Here we investigate this phenomenon by focusing on the genetic background of this correlation in order to understand the similarities and differences in the genetic regulation of these omics layers.
We performed locus-wide association studies of 92 protein levels measured in whole blood for 2,014 samples of European ancestry and found that 66 are genetically regulated. Three female- and one male-specific effects were detected. We estimated the genetically regulated GE for all significant genes in 49 GTEx v8 tissues. A total of 7 proteins showed negative correlations with their respective GE across multiple tissues. Finally, we tested for causal links of GE on protein expression via Mendelian Randomization, and confirmed a negative causal effect of GE on protein level for five of these genes in a total of 63 gene-tissue pairs: BLMH, CASP3, CXCL16, IL6R, and SFTPD. For IL6R, we replicated the negative causal effect on coronary-artery disease (CAD), while its GE was positively linked to CAD.
While total GE and protein levels are only weakly correlated, we found high correlations between their genetically regulated components across multiple tissues. Of note, strong negative causal effects of tissue-specific GE on five protein levels were detected. Causal network analyses revealed that GE effects on CAD risks was in general mediated by protein levels.
尽管基因表达（GE）和蛋白质水平通常受到强烈的遗传调控，但它们之间的相关性较低。在这里，我们通过关注这种相关性的遗传背景来研究这一现象，以了解这些组学层面的遗传调控的相似性和差异。
我们对 2014 个欧洲血统的全血样本中的 92 种蛋白质水平进行了全基因组关联研究，发现其中 66 种受到遗传调控。检测到三个女性特异性和一个男性特异性效应。我们估计了 49 个 GTEx v8 组织中所有显著基因的遗传调控 GE。共有 7 种蛋白质在多个组织中表现出与各自 GE 的负相关。最后，我们通过孟德尔随机化测试了 GE 对蛋白质表达的因果关系，并在总共 63 个基因-组织对中证实了其中 5 个基因的 GE 对蛋白质水平的负因果作用：BLMH、CASP3、CXCL16、IL6R 和 SFTPD。对于 IL6R，我们复制了其对冠心病（CAD）的负因果效应，而其 GE 与 CAD 呈正相关。
虽然总 GE 和蛋白质水平之间只有弱相关性，但我们发现多个组织之间其遗传调控成分之间存在高度相关性。值得注意的是，检测到组织特异性 GE 对五种蛋白质水平的强烈负因果效应。因果网络分析表明，GE 对 CAD 风险的影响通常通过蛋白质水平介导。
