Candidate pathway-based genome-wide association studies identify novel associations of genomic variants in the complement system associated with coronary artery disease.
Candidate pathway-based genome-wide association studies identify novel associations of genomic variants in the complement system associated with coronary artery disease.
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基于候选通路的全基因组关联研究确定了与冠状动脉疾病相关的补体系统中基因组变异的新关联
DOI：
10.1161/circgenetics.114.000738
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Wang QK
中科院分区：
文献类型：
--
作者：
Xu C;Yang Q;Xiong H;Wang L;Cai J;Wang F;Li S;Chen J;Wang C;Wang D;Xiong X;Wang P;Zhao Y;Wang X;Huang Y;Chen S;Yin D;Li X;Liu Y;Liu J;Wang J;Li H;Ke T;Ren X;Wu Y;Wu G;Wan J;Zhang R;Wu T;Wang J;Xia Y;Yang Y;Cheng X;Liao Y;Chen Q;Zhou Y;He Q;Tu X;Wang QK
全基因组关联研究发现的基因组变异解释了冠状动脉疾病(CAD)20%的遗传性，因此许多危险变异在CAD中仍然缺失。识别新的变异体可能揭开冠心病新的生物学途径和遗传机制。为了识别与CAD相关的新的变异，我们通过整合表达定量基因座(EQTL)分析和挖掘候选途径中的变异，开发了基于候选途径的GWAS。对GWAS数据进行挖掘，以分析32个补体系统基因的变异与冠心病的正相关性。然后，通过搜索现有的表达定量基因座数据库，确定具有正关联的基因的功能变异，并通过RT-PCR进行验证。随后采用后续病例对照设计来确定在两个独立的中国遗传ID人群中，功能变异是否与冠心病相关。基于候选途径的GWAS发现C3AR1和C6变异与冠心病之间存在正相关。C3AR1中的rs7842和C6中的rs4400166两个功能变异分别与C3AR1和C6的表达水平相关。在验证队列中，rs7842与冠心病显著相关(P=3.99×10−6，OR=1.47)，rs4400166与冠心病显著相关(P=9.30×10−3，OR=1.24)。Rs7842的P=1.53×10−5，OR=1.37；rs4400166的P=8.41×10−3，OR=1.21。将GWAs与生物学途径和eQTL相结合，可以有效地识别新的冠心病风险变量。增加C3AR1和C6表达的功能变异首次被证明具有显著的冠心病风险。
Genomic variants identified by genome-wide association studies (GWAS) explain <20% of heritability of coronary artery disease (CAD), thus many risk variants remain missing for CAD. Identification of new variants may unravel new biological pathways and genetic mechanisms for CAD. To identify new variants associated with CAD, we developed a candidate pathway-based GWAS by integrating expression quantitative loci (eQTL) analysis and mining of GWAS data with variants in a candidate pathway. Mining of GWAS data was performed to analyze variants in 32 complement system genes for positive association with CAD. Functional variants in genes showing positive association were then identified by searching existing expression quantitative loci databases and validated by RT-PCR. A follow-up case control design was then used to determine whether the functional variants are associated with CAD in two independent GeneID Chinese populations. Candidate pathway-based GWAS identified positive association between variants in C3AR1 and C6 and CAD. Two functional variants, rs7842 in C3AR1 and rs4400166 in C6, were found to be associated with expression levels of C3AR1 and C6, respectively. Significant association was identified between rs7842 and CAD (P=3.99×10−6, OR=1.47) and between rs4400166 and CAD (P=9.30×10−3, OR=1.24) in the validation cohort. The significant findings were confirmed in the replication cohort (P=1.53×10−5, OR=1.37 for rs7842; P=8.41×10−3, OR=1.21 for rs4400166. Integration of GWAS with biological pathways and eQTL is effective in identifying new risk variants for CAD. Functional variants increasing C3AR1 and C6 expression were shown to confer significant risk of CAD for the first time.
SNPExpress：全基因组基因型，拷贝数和基因表达水平的综合可视化。
影响因子：
4.4
作者：
Sanders MA;Verhaak RG;Geertsma-Kleinekoort WM;Abbas S;Horsman S;van der Spek PJ;Löwenberg B;Valk PJ
通讯作者：
Valk PJ