Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites

Tao Long; Michael Hicks; Hung Chun Yu; William H. Biggs; Ewen F. Kirkness; Cristina Menni; Jonas Zierer; Kerrin S. Small; Massimo Mangino; Helen Messier; Suzanne Brewerton; Yaron Turpaz; Brad A. Perkins; Anne M. Evans; Luke A D Miller; Lining Guo; C. Thomas Caskey; Nicholas J. Schork; Chad Garner; Tim D. Spector; J. Craig Venter; Amalio Telenti

doi:10.1038/ng.3809

Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites

Tao Long, Michael Hicks, Hung Chun Yu, William H. Biggs, Ewen F. Kirkness, Cristina Menni, Jonas Zierer, Kerrin S. Small, Massimo Mangino, Helen Messier, Suzanne Brewerton, Yaron Turpaz, Brad A. Perkins, Anne M. Evans, Luke A D Miller, Lining Guo, C. Thomas Caskey, Nicholas J. Schork, Chad Garner, Tim D. SpectorJ. Craig Venter^*, Amalio Telenti

^*Corresponding author for this work

Twin Research & Genetic Epidemiology

Research output: Contribution to journal › Article › peer-review

283 Citations (Scopus)

Abstract

Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10 -11). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.

Original language	English
Pages (from-to)	568-578
Number of pages	11
Journal	Nature Genetics
Volume	49
Issue number	4
Early online date	6 Mar 2017
DOIs	https://doi.org/10.1038/ng.3809
Publication status	Published - 30 Mar 2017

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Long, T., Hicks, M., Yu, H. C., Biggs, W. H., Kirkness, E. F., Menni, C., Zierer, J., Small, K. S., Mangino, M., Messier, H., Brewerton, S., Turpaz, Y., Perkins, B. A., Evans, A. M., Miller, L. A. D., Guo, L., Caskey, C. T., Schork, N. J., Garner, C., ... Telenti, A. (2017). Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nature Genetics, 49(4), 568-578. https://doi.org/10.1038/ng.3809

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title = "Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites",

abstract = "Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10 -11). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.",

author = "Tao Long and Michael Hicks and Yu, {Hung Chun} and Biggs, {William H.} and Kirkness, {Ewen F.} and Cristina Menni and Jonas Zierer and Small, {Kerrin S.} and Massimo Mangino and Helen Messier and Suzanne Brewerton and Yaron Turpaz and Perkins, {Brad A.} and Evans, {Anne M.} and Miller, {Luke A D} and Lining Guo and Caskey, {C. Thomas} and Schork, {Nicholas J.} and Chad Garner and Spector, {Tim D.} and Venter, {J. Craig} and Amalio Telenti",

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Long, T, Hicks, M, Yu, HC, Biggs, WH, Kirkness, EF, Menni, C , Zierer, J , Small, KS, Mangino, M, Messier, H, Brewerton, S, Turpaz, Y, Perkins, BA, Evans, AM, Miller, LAD, Guo, L, Caskey, CT, Schork, NJ, Garner, C, Spector, TD, Venter, JC & Telenti, A 2017, 'Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites', Nature Genetics, vol. 49, no. 4, pp. 568-578. https://doi.org/10.1038/ng.3809

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AU - Menni, Cristina

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AU - Perkins, Brad A.

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AU - Guo, Lining

AU - Caskey, C. Thomas

AU - Schork, Nicholas J.

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AU - Telenti, Amalio

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Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites

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