Mediation analysis demonstrates that trans-eQTLs are often explained by cis-mediation: a genome-wide analysis among 1,800 South Asians

A large fraction of human genes are regulated by genetic variation near the transcribed sequence (cis-eQTL, expression quantitative trait locus), and many cis-eQTLs have implications for human disease. Less is known regarding the effects of genetic variation on expression of distant genes (trans-eQTLs) and their biological mechanisms. In this work, we use genome-wide data on SNPs and array-based expression measures from mononuclear cells obtained from a population-based cohort of 1,799 Bangladeshi individuals to characterize cis- and trans-eQTLs and determine if observed trans-eQTL associations are mediated by expression of transcripts in cis with the SNPs showing trans-association, using Sobel tests of mediation. We observed 434 independent trans-eQTL associations at a false-discovery rate of 0.05, and 189 of these trans-eQTLs were also cis-eQTLs (enrichment P<0.0001). Among these 189 trans-eQTL associations, 39 were significantly attenuated after adjusting for a cis-mediator based ...

人类多数基因的表达均受转录序列附近遗传变异的调控，即顺式表达数量性状基因座（cis-eQTL），且诸多cis-eQTL与人类疾病存在密切关联。然而，人们对于遗传变异对远端基因表达的影响（即反式表达数量性状基因座，trans-eQTL）及其生物学机制的认知仍相对匮乏。本研究利用来自1799名孟加拉国个体的人群队列的单个核细胞中的全基因组单核苷酸多态性（SNPs）数据与基于基因芯片的表达量检测数据，对顺式与反式表达数量性状基因座进行系统表征，并借助中介分析的Sobel检验，探究已观测到的trans-eQTL关联是否由与该反式关联SNPs存在顺式关联的转录本表达所介导。本研究在假发现率（false discovery rate，FDR）0.05的阈值下共鉴定得到434个独立的trans-eQTL关联，其中189个同时属于cis-eQTL（富集检验P<0.0001）。在这189个trans-eQTL关联中，有39个在针对顺式中介因子进行校正后，其关联信号显著减弱……