Dissecting the Genetics of the Human Transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci

Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2,112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters, and enrichment of co-localised functional elements. We found eQTLs for about 85% of analysed genes, 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 MB to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might often be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels, and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. We show for strongly heritable transcripts that a considerable gap still exists between total heritability resulting from all trans-chromosomes and explained variance of all identified trans-eSNPs. In contrast, the vast majority of most cis-heritability of these genes is already explained. Dissection of co-localised functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene-expression, pathways and disease related processes. Gene expression from human blood mononuclear cells from individuals of the Leipzig LIFE Heart Study was analyzed applying Illumina HT-12 v4 Expression BeadChips. After preprocessing, 28,295 expression probes for 2,112 individuals remained for analysis. In a population-based analysis, we identified associations between DNA variants and RNA expression levels and characterized these findings.

表达数量性状基因座（expression Quantitative Trait Loci，以下简称eQTLs）相关研究已被证明是解析生物学通路与性状相关单核苷酸多态性（Single Nucleotide Polymorphism，以下简称SNP，复数形式为SNPs）致病机制的不可或缺工具。然而，多数全基因组eQTL研究的统计效力仍较为有限。本研究针对2112名个体的外周血单个核细胞（peripheral blood mononuclear cells，以下简称PBMC）开展了大规模eQTL分析，提升了全基因组范围内反式效应的检测效力。本研究跳出单变量SNP-转录本关联分析的框架，解析了eQTL与生物学通路的关联、表达调控的多基因效应、反式调控簇，以及共定位功能元件的富集特征。

本研究在约85%的分析基因中检测到了eQTL，其中18%的基因存在反式调控现象。距转录本5Mb范围内的局部eSNP呈现显著富集，这一结果挑战了当前顺式调控常用的区间范围。针对与全基因组关联研究（Genome-Wide Association Study，以下简称GWAS）相关的eSNP所调控的基因进行通路富集分析，验证了所鉴定eQTL的功能相关性。本研究证实，GWAS-SNP的邻近基因往往并非可靠的功能候选靶点。我们还鉴定出多个与多种表型（包括肥胖相关性状、高密度脂蛋白胆固醇水平及血液学表型）的GWAS-SNP存在潜在功能关联的新型反式调控簇。本研究借助染色质免疫沉淀（Chromatin Immunoprecipitation，以下简称ChIP）数据验证了相关生物学效应。针对高遗传力转录本的分析显示，所有跨染色体位点带来的总遗传力与已鉴定的所有反式eSNP所能解释的变异量之间仍存在显著缺口；与之相反，这些基因的绝大多数顺式遗传力已得到充分解释。对共定位功能元件的拆解分析表明，假基因位点与非编码RNA区域内的SNP在编码基因的调控中发挥着重要作用。

综上，本研究极大扩充了人类eQTL收录集，并加深了我们对基因表达、生物学通路及疾病相关过程的复杂遗传调控机制的理解。

本研究针对莱比锡LIFE心脏研究队列中受试者的外周血单个核细胞基因表达数据进行分析，采用的实验平台为Illumina HT-12 v4表达微珠芯片。经预处理后，最终保留2112名个体的28295个表达探针用于后续分析。在基于人群的分析中，我们鉴定出DNA变异与RNA表达水平之间的关联，并对上述结果进行了系统表征。