Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.
Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.
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DOI：
10.1161/circresaha.117.312086
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发表时间：
2018-02-02
影响因子：
20.1
通讯作者：
Verweij N
中科院分区：
文献类型：
--
作者：
van der Harst P;Verweij N
文本中提供了补充数字内容。冠状动脉疾病（CAD）是一种由遗传和环境因素驱动的复杂表型。迄今为止，已鉴定出 97 个遗传风险位点，但其他易感性位点的鉴定对于增强我们对 CAD 遗传结构的理解可能很重要。扩大全基因组重要基因座的数量，对功能见解进行分类，并增强我们对 CAD 遗传结构的理解。我们对英国生物银行资源的 34-541 个 CAD 病例和 261-984 个对照进行了全基因组关联研究，然后在 CARDIoGRAMplusC4D 的 88-192 个病例和 162-544 个对照中进行了复制。我们在荟萃分析中确定了 75 个可复制且在全基因组范围内显着的位点 (P<5×10−8)，其中 13 个以前未曾报道过。接下来，为了进一步识别新的位点，我们在 CARDIoGRAMplusC4D 数据中识别了所有有希望的（P<0.0001）位点，并与 UK Biobank 进行了相互复制和荟萃分析。这导致在荟萃分析中鉴定出另外 21 个达到全基因组显着性的新位点 (P<5×10−8)。最后，我们对所有可用数据进行了全基因组荟萃分析，揭示了 30 个额外的新位点 (P<5×10−8)，而无需进一步复制。英国生物银行样本量的增加使重建基因集的数量从 CAD 涉及的所有基因集的 4.2% 增加到 13.9%。对于 64 个新基因座，优先考虑了 155 个候选因果基因，其中许多与 CAD 没有明显的联系。对 161 个 CAD 基因座进行精细定位，生成了一系列可靠的单一因果变异和基因列表，用于功能跟踪。 CAD 的遗传风险变异与心房颤动、心力衰竭和死亡的发生有关。我们确定了 64 个新的 CAD 遗传风险位点，并对所有 161 个风险位点进行了精细绘图，以获得一组可靠的因果变异。重组基因集的大规模扩展支持对 CAD 遗传结构的扩展全基因模型观点。
Supplemental Digital Content is available in the text. Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD. We performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant (P<5×10−8) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising (P<0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance (P<5×10−8) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci (P<5×10−8) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death. We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD.