Vaez Ahmad, Jansen Rick, Prins Bram P, Hottenga Jouke-Jan, de Geus Eco J C, Boomsma Dorret I, Penninx Brenda W J H, Nolte Ilja M, Snieder Harold, Alizadeh Behrooz Z
From the Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen (A.V., B.P.P., I.M.N., H.S., B.Z.A.); Department of Psychiatry, VU University Medical Center, Amsterdam (R.J., B.W.J.H.P.); and Neuroscience Campus Amsterdam, VU University and VU University Medical Center, Amsterdam (R.J., J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), EMGO+ Institute, VU University and VU University Medical Center, Amsterdam (J.-J.H., E.J.C.d.G., D.I.B., B.W.J.H.P.), Department of Biological Psychology, VU University, Amsterdam, the Netherlands (J.-J.H., E.J.C.d.G., D.I.B.); and School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran (A.V.).
Circ Cardiovasc Genet. 2015 Jun;8(3):487-97. doi: 10.1161/CIRCGENETICS.114.000714. Epub 2015 Mar 9.
Genome-wide association studies (GWASs) have successfully identified several single nucleotide polymorphisms (SNPs) associated with serum levels of C-reactive protein (CRP). An important limitation of GWASs is that the identified variants merely flag the nearby genomic region and do not necessarily provide a direct link to the biological mechanisms underlying their corresponding phenotype. Here we apply a bioinformatics-based approach to uncover the functional characteristics of the 18 SNPs that had previously been associated with CRP at a genome-wide significant level.
In the first phase of in silico sequencing, we explore the vicinity of GWAS SNPs to identify all linked variants. In the second phase of expression quantitative trait loci analysis, we attempt to identify all nearby genes whose expression levels are associated with the corresponding GWAS SNPs. These 2 phases generate several relevant genes that serve as input to the next phase of functional network analysis. Our in silico sequencing analysis using 1000 Genomes Project data identified 7 nonsynonymous SNPs, which are in moderate to high linkage disequilibrium (r(2)>0.5) with the GWAS SNPs. Our expression quantitative trait loci analysis, which was based on one of the largest single data sets of genome-wide expression probes (n>5000) identified 23 significantly associated expression probes belonging to 15 genes (false discovery rate <0.01). The final phase of functional network analysis revealed 93 significantly enriched biological processes (false discovery rate <0.01).
Our post-GWAS analysis of CRP GWAS SNPs confirmed the previously known overlap between CRP and lipids biology. Additionally, it suggested an important role for interferons in the metabolism of CRP.
全基因组关联研究（GWAS）已成功鉴定出多个与血清C反应蛋白（CRP）水平相关的单核苷酸多态性（SNP）。GWAS的一个重要局限性在于，所鉴定的变异仅标记了附近的基因组区域，并不一定能直接揭示其相应表型背后的生物学机制。在此，我们应用一种基于生物信息学的方法来揭示先前在全基因组显著水平上与CRP相关的18个SNP的功能特征。
在计算机模拟测序的第一阶段，我们探索GWAS SNP的附近区域以鉴定所有连锁变异。在表达数量性状位点分析的第二阶段，我们试图鉴定所有表达水平与相应GWAS SNP相关的附近基因。这两个阶段产生了几个相关基因，作为功能网络分析下一阶段的输入。我们使用千人基因组计划数据进行的计算机模拟测序分析鉴定出7个非同义SNP，它们与GWAS SNP处于中度至高度连锁不平衡（r²>0.5）。我们基于最大的全基因组表达探针单数据集之一（n>5000）进行的表达数量性状位点分析，鉴定出属于15个基因的23个显著相关的表达探针（错误发现率<0.01）。功能网络分析的最后阶段揭示了93个显著富集的生物学过程（错误发现率<0.01）。
我们对CRP的GWAS SNP进行的GWAS后分析证实了CRP与脂质生物学之间先前已知的重叠。此外，它还提示了干扰素在CRP代谢中的重要作用。
