Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression
Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression
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DOI：
10.1016/j.ajhg.2017.04.016
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发表时间：
2017-06-01
影响因子：
9.8
通讯作者：
Roussos, Panos
中科院分区：
文献类型：
--
作者：
Hauberg, Mads Engel;Zhang, Wen;Roussos, Panos
全基因组关联研究（GWAS）已经确定了许多与性状和疾病有关的遗传位点。然而，通常不清楚这些基因座中哪些基因受到影响，以及相关的遗传变异是否导致基因功能增加或减少。为了缓解这一问题，我们使用孟德尔随机化方法，将 57 个 GWAS 中常见遗传变异的关联与来自广泛组织的表达数量性状位点 (eQTL) 的 24 项研究进行了整合。我们总共发现了 3,484 个与基因性状相关的表达变化实例，错误发现率 < 0.05。这些基因通常与遗传变异并不最接近，并且主要在源自病理生理相关组织的 eQTL 中被识别。例如，与脂质特征相关的表达变化的基因主要在肝脏中发现，而与心血管疾病相关的基因则在动脉组织中发现。受影响的基因还指向与所研究的性状有关的生物过程，例如类风湿性关节炎中的白介素 27 通路。此外，比较不同性状中与性状相关的基因表达变化表明多效性是一种普遍现象，并指出了激动性和拮抗性多效性的具体实例。例如，SNX19和ABCB9的表达与精神分裂症风险和教育程度呈正相关。为了便于解释，我们提供了这个关于常见性状相关遗传变异如何改变各种组织中基因表达的词典作为在线数据库 GWAS2Genes。
Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach. We discovered a total of 3,484 instances of gene-trait-associated changes in expression at a false-discovery rate < 0.05. These genes were often not closest to the genetic variant and were primarily identified in eQTLs derived from pathophysiologically relevant tissues. For instance, genes with expression changes associated with lipid traits were mostly identified in the liver, and those associated with cardiovascular disease were identified in arterial tissue. The affected genes additionally point to biological processes implicated in the interrogated traits, such as the interleukin-27 pathway in rheumatoid arthritis. Further, comparing trait-associated gene expression changes across traits suggests that pleiotropy is a widespread phenomenon and points to specific instances of both agonistic and antagonistic pleiotropy. For instance, expression of SNX19 and ABCB9 is positively correlated with both the risk of schizophrenia and educational attainment. To facilitate interpretation, we provide this lexicon of how common trait-associated genetic variants alter gene expression in various tissues as the online database GWAS2Genes.