Hauberg Mads Engel, Zhang Wen, Giambartolomei Claudia, Franzén Oscar, Morris David L, Vyse Timothy J, Ruusalepp Arno, Sklar Pamela, Schadt Eric E, Björkegren Johan L M, Roussos Panos
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lundbeck Foundation Initiative of Integrative Psychiatric Research, Aarhus University, Aarhus 8000, Denmark; Centre for Integrative Sequencing, Aarhus University, Aarhus 8000, Denmark.
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Am J Hum Genet. 2017 Jun 1;100(6):885-894. doi: 10.1016/j.ajhg.2017.04.016. Epub 2017 May 25.
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.
全基因组关联研究（GWAS）已经确定了许多与性状和疾病相关的基因座。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导致基因功能增加还是减少。为了缓解这一问题，我们使用孟德尔随机化方法，将57项GWAS中常见遗传变异的关联与来自广泛组织的24项表达定量性状基因座（eQTL）研究进行整合。我们共发现了3484例基因-性状相关的表达变化，错误发现率<0.05。这些基因通常并非最接近遗传变异的基因，且主要在源自病理生理相关组织的eQTL中被鉴定出来。例如，与脂质性状相关的表达变化基因大多在肝脏中被鉴定出来，而与心血管疾病相关的基因则在动脉组织中被鉴定出来。受影响的基因还指向了所研究性状涉及的生物学过程，比如类风湿性关节炎中的白细胞介素-27途径。此外，比较不同性状间与性状相关的基因表达变化表明，多效性是一种普遍现象，并指出了协同多效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受教育程度均呈正相关。为便于解读，我们将这个关于常见性状相关遗传变异如何在各种组织中改变基因表达的词汇表作为在线数据库GWAS2Genes提供。
