Yang Fan, Gleason Kevin J, Wang Jiebiao, Duan Jubao, He Xin, Pierce Brandon L, Chen Lin S
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA.
Bioinformatics. 2021 Sep 9;37(17):2513-2520. doi: 10.1093/bioinformatics/btab139.
Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cis-gene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and trans-associations mediated by cis-gene expression also have effects shared across relevant conditions.
We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmedmost and CCmedspec for detecting cross-tissue and tissue-specific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated trans-associations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues.
CCmed software is available at http://github.com/kjgleason/CCmed.
Supplementary data are available at Bioinformatics online.
反式作用表达数量性状位点（eQTL）共同解释了相当一部分的表达变异，但由于其效应通常个体较弱，因此难以检测和重复验证。对远端基因的大部分遗传效应是通过顺式基因表达介导的。顺式关联（单核苷酸多态性与顺式基因之间）以及基于单核苷酸多态性基因型的基因-基因相关性可以建立反式关联（单核苷酸多态性与反式基因之间）。顺式关联和基因-基因条件相关性在相关组织和条件下具有共享效应，并且由顺式基因表达介导的反式关联在相关条件下也具有共享效应。
我们提出了一种跨条件中介分析方法（CCmed），用于在相关条件/研究中检测具有可重复效应的顺式介导反式关联。CCmed整合了来自多个组织/研究的顺式关联和基因-基因条件相关性统计数据。受eQTL的双峰效应共享模式的启发，我们提出了CCmed的两种变体，即CCmedmost和CCmedspec，分别用于检测跨组织和组织特异性反式关联。我们分析了基因型-组织表达（GTEx）项目中13种脑组织的数据，并确定了跨脑组织具有顺式介导反式关联的三联体，其中许多在两项重复研究中显示出反式关联的证据。我们还确定了至少在两种脑组织中与精神分裂症位点相关的反式基因。
CCmed软件可在http://github.com/kjgleason/CCmed获取。
补充数据可在《生物信息学》在线获取。
