Integrative genomic analysis of blood pressure and related phenotypes in rats.
Integrative genomic analysis of blood pressure and related phenotypes in rats.
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DOI：
10.1242/dmm.048090
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发表时间：
2021-05-01
影响因子：
4.3
通讯作者：
Kato N
中科院分区：
文献类型：
--
作者：
Takeuchi F;Liang YQ;Isono M;Tajima M;Cui ZH;Iizuka Y;Gotoda T;Nabika T;Kato N
尽管人类全基因组关联研究取得了显著进展，但遗传关联的统计证据与对这些关联的潜在机制的功能理解之间仍存在很大差距。作为弥合这一差距的一种手段，我们进行了血压（BP）和相关表型的基因组分析在自发性高血压大鼠（SHR）和他们的亚株，易卒中的SHR（SHRSP），这两个独特的遗传模型，严重的高血压和心血管并发症。通过整合全基因组测序、转录组分析、全基因组连锁扫描（最大n=1415）、精细同源作图（最大n=8704）、药物干预和与全转录组关联研究（TWAS）数据集的比较分析，我们搜索了测试性状的因果基因和因果通路。与非高血压对照品系Wistar京都大鼠（WKY）相比，总体结果验证了血压升高的多基因结构;例如，SHRSP和WKY之间的品系间血压差异在很大程度上可以通过7种SHRSP衍生的同源品系中血压变化的集合来解释。我们确定了26个潜在的靶基因，包括人类TWAS基因座的大鼠同源基因，用于测试性状。在这项研究中，我们重新发现了18个基因，这些基因以前被确定为与高血压或心血管表型有关。值得注意的是，这些基因中有5个属于激肽释放酶-激肽/肾素-血管紧张素系统（KKS/RAS），其中高血压和非高血压等位基因之间最显著的差异表达可以在大鼠Klk 1旁系同源物中检测到。结合药物干预，我们提供了体内实验证据，支持在大鼠多基因高血压模型中存在关键疾病途径，如KKS/RAS。总结：基因组测序，转录组分析和遗传作图，利用人类全转录组关联研究数据，确定了26个潜在的靶基因，调节高血压动物模型中的血压和相关表型。
Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n=1415), fine congenic mapping (maximum n=8704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g. inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein–kinin/renin–angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model. Summary: Genome sequencing, transcriptome profiling and genetic mapping, with utilization of human transcriptome-wide association study data, identified 26 potential target genes that regulate blood pressure and related phenotypes in an animal model of hypertension.
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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
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
DOI：
10.1073/pnas.0407234102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Chan, JCY;Knudson, O;Wu, QY
通讯作者：
Wu, QY
影响因子：
8.3
作者：
Frantz, SA;Kaiser, M;Samani, NJ
通讯作者：
Samani, NJ
影响因子：
5.4
作者：
Inomata, H;Watanabe, T;Kato, N
通讯作者：
Kato, N