高通量测序的系统生物学揭示了里昂高血压大鼠代谢综合征的潜在遗传机制。
Systems biology with high-throughput sequencing reveals genetic mechanisms underlying the metabolic syndrome in the Lyon hypertensive rat.
作者信息
Wang Jinkai, Ma Man Chun John, Mennie Amanda K, Pettus Janette M, Xu Yang, Lin Lan, Traxler Matthew G, Jakoubek Jessica, Atanur Santosh S, Aitman Timothy J, Xing Yi, Kwitek Anne E
机构信息
From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
出版信息
Circ Cardiovasc Genet. 2015 Apr;8(2):316-26. doi: 10.1161/CIRCGENETICS.114.000520. Epub 2015 Jan 8.
BACKGROUND
The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon hypertensive and Lyon normotensive rats are models of MetS sensitivity and resistance, respectively. To identify genetic determinants and mechanisms underlying MetS, an F2 intercross between Lyon hypertensive and Lyon normotensive was comprehensively studied.
METHODS AND RESULTS
Multidimensional data were obtained including genotypes of 1536 single-nucleotide polymorphisms, 23 physiological traits, and >150 billion nucleotides of RNA-seq reads from the livers of F2 intercross offspring and parental rats. Phenotypic and expression quantitative trait loci (eQTL) were mapped. Application of systems biology methods identified 17 candidate MetS genes. Several putative causal cis-eQTL were identified corresponding with phenotypic QTL loci. We found an eQTL hotspot on rat chromosome 17 that is causally associated with multiple MetS-related traits and found RGD1562963, a gene regulated in cis by this eQTL hotspot, as the most likely eQTL driver gene directly affected by genetic variation between Lyon hypertensive and Lyon normotensive rats.
CONCLUSIONS
Our study sheds light on the intricate pathogenesis of MetS and demonstrates that systems biology with high-throughput sequencing is a powerful method to study the pathogenesis of complex genetic diseases.
背景
代谢综合征（MetS）是一组同时出现的复杂病症，包括肥胖、高血压、血脂异常和胰岛素抵抗。里昂高血压大鼠和里昂正常血压大鼠分别是MetS敏感性和抗性的模型。为了确定MetS潜在的遗传决定因素和机制，对里昂高血压大鼠和里昂正常血压大鼠之间的F2代杂交进行了全面研究。
方法与结果
获取了多维数据，包括1536个单核苷酸多态性的基因型、23个生理性状，以及来自F2代杂交后代和亲本大鼠肝脏的超过1500亿个核苷酸的RNA测序读数。绘制了表型和表达数量性状位点（eQTL）图谱。运用系统生物学方法鉴定出17个候选MetS基因。确定了几个与表型QTL位点相对应的假定因果顺式eQTL。我们在大鼠17号染色体上发现了一个eQTL热点，它与多个MetS相关性状存在因果关联，并发现RGD1562963，一个受该eQTL热点顺式调控的基因，是最有可能直接受里昂高血压大鼠和里昂正常血压大鼠之间遗传变异影响的eQTL驱动基因。
结论
我们的研究揭示了MetS复杂的发病机制，并证明高通量测序的系统生物学是研究复杂遗传疾病发病机制的有力方法。
Zotero 插件