Systems Biology with High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat

Jinkai Wang; Man Chun John Ma; Amanda K Mennie; Janette M Pettus; Yang Xu; Lan Lin; Matthew G Traxler; Jessica Jakoubek; Santosh S Atanur; Timothy J Aitman; Yi Xing; Anne E Kwitek

doi:10.1161/CIRCGENETICS.114.000520

Systems Biology with High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat

Jinkai Wang, Man Chun John Ma, Amanda K Mennie, Janette M Pettus, Yang Xu, Lan Lin, Matthew G Traxler, Jessica Jakoubek, Santosh S Atanur, Timothy J Aitman, Yi Xing, Anne E Kwitek

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Abstract / Description of output

BACKGROUND: -The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon Hypertensive (LH) and Lyon Normotensive (LN) rats are models of MetS sensitivity and resistance, respectively. To identify genetic determinants and mechanisms underlying MetS, an F2 intercross between LH and LN was comprehensively studied.

METHODS AND RESULTS: -Multi-dimensional data were obtained including genotypes of 1536 SNPs, 23 physiological traits and more than 150 billion nucleotides of RNA-seq reads from the livers of F2 intercross offspring and parental rats. Phenotypic and expression QTL were mapped. Application of systems biology methods identified 17 candidate MetS genes. Several putative causal cis-eQTL were identified corresponding with pQTL 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 LH and LN 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 etiology of complex genetic diseases.

Original language	English
Journal	Circulation: Cardiovascular Genetics
DOIs	https://doi.org/10.1161/CIRCGENETICS.114.000520
Publication status	Published - 8 Jan 2015

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10.1161/CIRCGENETICS.114.000520

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Wang, J., Ma, M. C. J., Mennie, A. K., Pettus, J. M., Xu, Y., Lin, L., Traxler, M. G., Jakoubek, J., Atanur, S. S., Aitman, T. J., Xing, Y., & Kwitek, A. E. (2015). Systems Biology with High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat. Circulation: Cardiovascular Genetics. https://doi.org/10.1161/CIRCGENETICS.114.000520

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title = "Systems Biology with High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat",

abstract = "BACKGROUND: -The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon Hypertensive (LH) and Lyon Normotensive (LN) rats are models of MetS sensitivity and resistance, respectively. To identify genetic determinants and mechanisms underlying MetS, an F2 intercross between LH and LN was comprehensively studied.METHODS AND RESULTS: -Multi-dimensional data were obtained including genotypes of 1536 SNPs, 23 physiological traits and more than 150 billion nucleotides of RNA-seq reads from the livers of F2 intercross offspring and parental rats. Phenotypic and expression QTL were mapped. Application of systems biology methods identified 17 candidate MetS genes. Several putative causal cis-eQTL were identified corresponding with pQTL 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 LH and LN 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 etiology of complex genetic diseases.",

author = "Jinkai Wang and Ma, {Man Chun John} and Mennie, {Amanda K} and Pettus, {Janette M} and Yang Xu and Lan Lin and Traxler, {Matthew G} and Jessica Jakoubek and Atanur, {Santosh S} and Aitman, {Timothy J} and Yi Xing and Kwitek, {Anne E}",

year = "2015",

month = jan,

day = "8",

doi = "10.1161/CIRCGENETICS.114.000520",

language = "English",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

}

TY - JOUR

T1 - Systems Biology with High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat

AU - Wang, Jinkai

AU - Ma, Man Chun John

AU - Mennie, Amanda K

AU - Pettus, Janette M

AU - Xu, Yang

AU - Lin, Lan

AU - Traxler, Matthew G

AU - Jakoubek, Jessica

AU - Atanur, Santosh S

AU - Aitman, Timothy J

AU - Xing, Yi

AU - Kwitek, Anne E

PY - 2015/1/8

Y1 - 2015/1/8

N2 - BACKGROUND: -The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon Hypertensive (LH) and Lyon Normotensive (LN) rats are models of MetS sensitivity and resistance, respectively. To identify genetic determinants and mechanisms underlying MetS, an F2 intercross between LH and LN was comprehensively studied.METHODS AND RESULTS: -Multi-dimensional data were obtained including genotypes of 1536 SNPs, 23 physiological traits and more than 150 billion nucleotides of RNA-seq reads from the livers of F2 intercross offspring and parental rats. Phenotypic and expression QTL were mapped. Application of systems biology methods identified 17 candidate MetS genes. Several putative causal cis-eQTL were identified corresponding with pQTL 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 LH and LN 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 etiology of complex genetic diseases.

AB - BACKGROUND: -The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon Hypertensive (LH) and Lyon Normotensive (LN) rats are models of MetS sensitivity and resistance, respectively. To identify genetic determinants and mechanisms underlying MetS, an F2 intercross between LH and LN was comprehensively studied.METHODS AND RESULTS: -Multi-dimensional data were obtained including genotypes of 1536 SNPs, 23 physiological traits and more than 150 billion nucleotides of RNA-seq reads from the livers of F2 intercross offspring and parental rats. Phenotypic and expression QTL were mapped. Application of systems biology methods identified 17 candidate MetS genes. Several putative causal cis-eQTL were identified corresponding with pQTL 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 LH and LN 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 etiology of complex genetic diseases.

U2 - 10.1161/CIRCGENETICS.114.000520

DO - 10.1161/CIRCGENETICS.114.000520

M3 - Article

C2 - 25573024

SN - 1942-325X

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

ER -

Systems Biology with High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat

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