The HDAC9-associated risk locus promotes coronary artery disease by governing TWIST1.
The HDAC9-associated risk locus promotes coronary artery disease by governing TWIST1.
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DOI：
10.1371/journal.pgen.1010261
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发表时间：
2022-06
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
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全基因组关联研究（GWAS）已经确定了数千个与常见疾病风险相关的单核苷酸多态性（SNP）。然而，由于这些风险SNP中的绝大多数位于基因编码区之外，GWAS通常不能提供关于受影响的特定基因或这些候选基因发挥作用的组织的因果机制的信息。了解致病基因及其作用机制的“黄金标准”方法是费力的基础科学研究，通常涉及复杂的敲入或敲除小鼠品系，然而，这些类型的研究作为高通量手段来了解导致冠状动脉疾病（CAD）等复杂疾病的许多风险变体是不切实际的。作为一种解决方案，我们开发了一个精简的、数据驱动的信息学管道，以获得对复杂遗传基因座的机理见解。该管道首先从了解给定位点的SNP的相对位置和连锁不平衡关系开始，然后识别附近的表达数量性状位点（eQTL），以确定它们的相对独立性和介导其疾病因果效应的可能组织。然后，该管道试图了解与其他疾病相关基因，疾病亚表型，潜在因果关系（孟德尔随机化）的关联，以及这些基因在基因调控共表达网络（GRNs）中的调控和功能参与。在这里，我们应用这个管道来了解与CAD相关的一组SNP，这些SNP位于编码HDAC9的基因内并紧邻该基因。我们的管道证明，并验证，该基因座是CAD的原因，通过调节动脉壁中的TWIST 1表达水平，并通过控制与骨骼肌代谢功能相关的GRN。我们的结果与许多先前的研究相一致，并且还提供了明确的证据，表明该位点不控制HDAC9的表达，结构或功能。这种管道应该被认为是一种强大而有效的方式来了解GWAS风险位点，以更好地反映与常见疾病相关的遗传风险的高度复杂性。全基因组关联研究（GWAS）已经确定了数千个与常见疾病风险相关的单核苷酸多态性（SNP）。然而，对于绝大多数这些SNP，关于受影响的特定基因或这些候选基因发挥其作用的组织的因果机制是未知的。作为一种解决方案，我们开发了一个精简的、数据驱动的信息学管道，以获得对复杂遗传基因座的机理见解。在这里，我们应用这个管道来了解与编码HDAC9的基因内和紧邻的冠状动脉疾病（CAD）相关的一组SNP。我们的管道证明，并验证，该基因座是CAD的原因，通过调节动脉壁中的TWIST 1基因表达水平，并通过控制与骨骼肌代谢功能相关的基因调控共表达网络。我们的结果与许多先前的研究相一致，并且还表明该位点不控制HDAC9的表达、结构或功能。这个管道应该被认为是一个强大而有效的方式来了解GWAS风险位点。
Genome wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with the risk of common disorders. However, since the large majority of these risk SNPs reside outside gene-coding regions, GWAS generally provide no information about causal mechanisms regarding the specific gene(s) that are affected or the tissue(s) in which these candidate gene(s) exert their effect. The ‘gold standard’ method for understanding causal genes and their mechanisms of action are laborious basic science studies often involving sophisticated knockin or knockout mouse lines, however, these types of studies are impractical as a high-throughput means to understand the many risk variants that cause complex diseases like coronary artery disease (CAD). As a solution, we developed a streamlined, data-driven informatics pipeline to gain mechanistic insights on complex genetic loci. The pipeline begins by understanding the SNPs in a given locus in terms of their relative location and linkage disequilibrium relationships, and then identifies nearby expression quantitative trait loci (eQTLs) to determine their relative independence and the likely tissues that mediate their disease-causal effects. The pipeline then seeks to understand associations with other disease-relevant genes, disease sub-phenotypes, potential causality (Mendelian randomization), and the regulatory and functional involvement of these genes in gene regulatory co-expression networks (GRNs). Here, we applied this pipeline to understand a cluster of SNPs associated with CAD within and immediately adjacent to the gene encoding HDAC9. Our pipeline demonstrated, and validated, that this locus is causal for CAD by modulation of TWIST1 expression levels in the arterial wall, and by also governing a GRN related to metabolic function in skeletal muscle. Our results reconciled numerous prior studies, and also provided clear evidence that this locus does not govern HDAC9 expression, structure or function. This pipeline should be considered as a powerful and efficient way to understand GWAS risk loci in a manner that better reflects the highly complex nature of genetic risk associated with common disorders. Genome wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with the risk of common disorders. However, for the great majority of these SNPs, the causal mechanisms regarding the specific gene(s) that are affected or the tissue(s) in which these candidate gene(s) exert their effect are unknown. As a solution, we developed a streamlined, data-driven informatics pipeline to gain mechanistic insights on complex genetic loci. Here, we applied this pipeline to understand a cluster of SNPs associated with coronary artery disease (CAD) within and immediately adjacent to the gene encoding HDAC9. Our pipeline demonstrated, and validated, that this locus is causal for CAD by modulation of TWIST1 gene expression levels in the arterial wall, and by also governing a gene regulatory co-expression network related to metabolic function in skeletal muscle. Our results reconciled numerous prior studies, and also demonstrated that this locus does not govern HDAC9 expression, structure or function. This pipeline should be considered as a powerful and efficient way to understand GWAS risk loci.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
4.5
作者：
Hirsch N;Eshel R;Bar Yaacov R;Shahar T;Shmulevich F;Dahan I;Levaot N;Kaplan T;Lupiáñez DG;Birnbaum RY
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Birnbaum RY
影响因子：
14.9
作者：
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通讯作者：
Pesole G
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
DOI：
10.1126/science.aad6970
发表时间：
2016-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franzén O;Ermel R;Cohain A;Akers NK;Di Narzo A;Talukdar HA;Foroughi-Asl H;Giambartolomei C;Fullard JF;Sukhavasi K;Köks S;Gan LM;Giannarelli C;Kovacic JC;Betsholtz C;Losic B;Michoel T;Hao K;Roussos P;Skogsberg J;Ruusalepp A;Schadt EE;Björkegren JL
通讯作者：
Björkegren JL