A robust two-sample transcriptome-wide Mendelian randomization method integrating GWAS with multi-tissue eQTL summary statistics.
A robust two-sample transcriptome-wide Mendelian randomization method integrating GWAS with multi-tissue eQTL summary statistics.
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将GWAS与多组织eQTL汇总统计相结合的稳健的双样本全转录组孟德尔随机化方法。
DOI：
10.1002/gepi.22380
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发表时间：
2021-06
影响因子：
2.1
通讯作者：
Chen, Lin S.
中科院分区：
文献类型：
--
作者：
Gleason, Kevin J.;Yang, Fan;Chen, Lin S.
关键词：
通过将遗传变异视为工具变量（IV），双样本孟德尔随机化（MR）方法仅使用汇总统计量检测复杂疾病的遗传调节风险暴露。在全转录组MR（transmitome-wide MR，TWMR）分析中，将基因表达量作为暴露量时，eQTL（expression-quantitative-trait-loci）可能具有多效性，或者与非通过表达量对疾病产生影响的变异体相关，这些无效IV的存在会导致有偏倚的推断。此外，作为基因IV的eQTL的数量通常是有限的，使得无效IV的检测具有挑战性。我们提出了一种方法，“MR-MtRobin”，在存在无效IV的情况下准确的TWMR推断。该方法利用混合模型中的多组织eQTL数据，从eQTL汇总统计量的估计误差中识别出因多效性引起的IV特异性随机效应，并在存在无效IV的情况下，对eQTL和GWAS（genome wide association study）效应之间的依赖性（固定效应）提供准确的推断。此外，我们的方法可以通过选择跨组织eQTL作为IV，提高了eQTL和GWAS数据之间的一致性效应，从而提高推断的能力和精度。我们应用MR-MtRobin通过整合精神病基因组学联盟和基因型组织表达项目（V8）的摘要级数据来检测与精神分裂症风险相关的基因。
By treating genetic variants as instrumental variables (IVs), two-sample Mendelian randomization (MR) methods detect genetically regulated risk exposures for complex diseases using only summary statistics. When considering gene expression as exposure in transcriptome-wide MR (TWMR) analyses, the eQTLs (expression-quantitative-trait-loci) may have pleiotropic effects or be correlated with variants that have effects on disease not via expression, and the presence of those invalid IVs would lead to biased inference. Moreover, the number of eQTLs as IVs for a gene is generally limited, making the detection of invalid IVs challenging. We propose a method, “MR-MtRobin,” for accurate TWMR inference in the presence of invalid IVs. By leveraging multi-tissue eQTL data in a mixed model, the proposed method makes identifiable the IV-specific random effects due to pleiotropy from estimation errors of eQTL summary statistics, and can provide accurate inference on the dependence (fixed effects) between eQTL and GWAS (genome-wide association study) effects in the presence of invalid IVs. Moreover, our method can improve power and precision in inference by selecting cross-tissue eQTLs as IVs that have improved consistency of effects across eQTL and GWAS data. We applied MR-MtRobin to detect genes associated with schizophrenia risk by integrating summary-level data from the Psychiatric Genomics Consortium and the Genotype-Tissue Expression project (V8).
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
DOI：
10.1097/ede.0000000000000559
发表时间：
2017-01
期刊：
Epidemiology (Cambridge, Mass.)
影响因子：
--
作者：
Burgess S;Bowden J;Fall T;Ingelsson E;Thompson SG
通讯作者：
Thompson SG
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
影响因子：
14.9
作者：
Jia, Peilin;Dai, Yulin;Zhao, Zhongming
通讯作者：
Zhao, Zhongming
Aly 和 THO 是人类 TREX 复合物组装以及 TREX 成分与剪接 mRNA 关联所必需的
影响因子：
14.9
作者：
Chi B;Wang Q;Wu G;Tan M;Wang L;Shi M;Chang X;Cheng H
通讯作者：
Cheng H