Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Xiaojing Chu; Martin Jaeger; Joep Beumer; Olivier B. Bakker; Raul Aguirre-Gamboa; Marije Oosting; Sanne P. Smeekens; Simone Moorlag; Vera P. Mourits; Valerie A. C. M. Koeken; Charlotte de Bree; Trees Jansen; Ian T. Mathews; Khoi Dao; Mahan Najhawan; Jeramie D. Watrous; Irma Joosten; Sonia Sharma; Hans J. P. M. Koenen; Sebo Withoff; Iris H. Jonkers; Romana T. Netea-Maier; Ramnik J. Xavier; Lude Franke; Cheng-Jian Xu; Leo A. B. Joosten; Serena Sanna; Mohit Jain; Vinod Kumar; Hans Clevers; Cisca Wijmenga; Mihai G. Netea; Yang Li

doi:10.1186/s13059-021-02413-z

Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Xiaojing Chu, Martin Jaeger, Joep Beumer, Olivier B. Bakker, Raul Aguirre-Gamboa, Marije Oosting, Sanne P. Smeekens, Simone Moorlag, Vera P. Mourits, Valerie A. C. M. Koeken, Charlotte de Bree, Trees Jansen, Ian T. Mathews, Khoi Dao, Mahan Najhawan, Jeramie D. Watrous, Irma Joosten, Sonia Sharma, Hans J. P. M. Koenen, Sebo WithoffIris H. Jonkers, Romana T. Netea-Maier, Ramnik J. Xavier, Lude Franke, Cheng-Jian Xu, Leo A. B. Joosten, Serena Sanna, Mohit Jain, Vinod Kumar, Hans Clevers, Cisca Wijmenga^*, Mihai G. Netea, Yang Li

^*Corresponding author for this work

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

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

31 Citations (Scopus)

129 Downloads (Pure)

Abstract

BACKGROUND: Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors.

RESULT: We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target.

CONCLUSION: This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.

Original language	English
Article number	198
Number of pages	22
Journal	Genome Biology
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s13059-021-02413-z
Publication status	Published - 6-Jul-2021

Keywords

Metabolomics
Genomics
Immune phenotypes
Integrative analysis
POLYUNSATURATED FATTY-ACIDS
WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
GENETIC-FACTORS
CROHNS-DISEASE
EXPRESSION
COMMON
VARIANTS
RARE
SUSCEPTIBILITY

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Additional file 13 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease
Mourits, V. P. (Contributor), Koenen, H. J. P. M. (Contributor), Netea, M. G. (Contributor), Magadi Gopalaiah, V. K. (Contributor), Xu, C.-J. (Contributor), Mathews, I. T. (Contributor), Jansen, T. (Contributor), Smeekens, S. P. (Contributor), Jaeger, M. (Contributor), Jain, M. (Contributor), Xavier, R. J. (Contributor), Withoff, S. (Contributor), Clevers, H. (Contributor), Netea-Maier, R. T. (Contributor), Chu, X. (Contributor), Joosten, L. A. B. (Contributor), Joosten, I. (Contributor), Li, Y. (Contributor), Sanna, S. (Contributor), Bakker, O. (Contributor), Watrous, J. D. (Contributor), Najhawan, M. (Contributor), Koeken, V. A. C. M. (Contributor), Dao, K. (Contributor), Aguirre-Gamboa, R. (Contributor), Sharma, S. (Contributor), Franke, L. (Contributor), Jonkers, I. (Contributor), Moorlag, S. (Contributor), de Bree, C. (Contributor), Beumer, J. (Contributor), Wijmenga, C. (Contributor) & Oosting, M. (Contributor), figshare Academic Research System, 7-Jul-2021
DOI: 10.6084/m9.figshare.14920800.v1, https://doi.org/10.6084%2Fm9.figshare.14920800.v1
Dataset
Additional file 2 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease
Sanna, S. (Contributor), Sharma, S. (Contributor), Koenen, H. J. P. M. (Contributor), Smeekens, S. P. (Contributor), Oosting, M. (Contributor), Netea, M. G. (Contributor), Dao, K. (Contributor), Joosten, L. A. B. (Contributor), Beumer, J. (Contributor), Wijmenga, C. (Contributor), Jain, M. (Contributor), Franke, L. (Contributor), Watrous, J. D. (Contributor), Li, Y. (Contributor), Joosten, I. (Contributor), Xavier, R. J. (Contributor), Jaeger, M. (Contributor), Bakker, O. (Contributor), Najhawan, M. (Contributor), Clevers, H. (Contributor), Magadi Gopalaiah, V. K. (Contributor), Chu, X. (Contributor), Mathews, I. T. (Contributor), Netea-Maier, R. T. (Contributor), Koeken, V. A. C. M. (Contributor), Aguirre-Gamboa, R. (Contributor), Withoff, S. (Contributor), Jansen, T. (Contributor), Jonkers, I. (Contributor), Xu, C.-J. (Contributor), Mourits, V. P. (Contributor), de Bree, C. (Contributor) & Moorlag, S. (Contributor), figshare Academic Research System, 7-Jul-2021
DOI: 10.6084/m9.figshare.14921230.v1, https://doi.org/10.6084%2Fm9.figshare.14921230.v1
Dataset
Additional file 9 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease
Moorlag, S. (Contributor), Magadi Gopalaiah, V. K. (Contributor), Clevers, H. (Contributor), Koenen, H. J. P. M. (Contributor), Aguirre-Gamboa, R. (Contributor), Sanna, S. (Contributor), Mourits, V. P. (Contributor), Withoff, S. (Contributor), Joosten, I. (Contributor), Netea, M. G. (Contributor), Bakker, O. (Contributor), Smeekens, S. P. (Contributor), Wijmenga, C. (Contributor), Oosting, M. (Contributor), Mathews, I. T. (Contributor), Jain, M. (Contributor), Chu, X. (Contributor), Jonkers, I. (Contributor), de Bree, C. (Contributor), Najhawan, M. (Contributor), Jansen, T. (Contributor), Beumer, J. (Contributor), Sharma, S. (Contributor), Jaeger, M. (Contributor), Koeken, V. A. C. M. (Contributor), Joosten, L. A. B. (Contributor), Netea-Maier, R. T. (Contributor), Xu, C.-J. (Contributor), Watrous, J. D. (Contributor), Xavier, R. J. (Contributor), Li, Y. (Contributor), Franke, L. (Contributor) & Dao, K. (Contributor), figshare Academic Research System, 7-Jul-2021
DOI: 10.6084/m9.figshare.14921251.v1, https://doi.org/10.6084%2Fm9.figshare.14921251.v1
Dataset

Cite this

Chu, X., Jaeger, M., Beumer, J., Bakker, O. B., Aguirre-Gamboa, R., Oosting, M., Smeekens, S. P., Moorlag, S., Mourits, V. P., Koeken, V. A. C. M., de Bree, C., Jansen, T., Mathews, I. T., Dao, K., Najhawan, M., Watrous, J. D., Joosten, I., Sharma, S., Koenen, H. J. P. M., ... Li, Y. (2021). Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease. Genome Biology, 22(1), Article 198. https://doi.org/10.1186/s13059-021-02413-z

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title = "Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease",

abstract = "BACKGROUND: Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors.RESULT: We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target.CONCLUSION: This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.",

keywords = "Metabolomics, Genomics, Immune phenotypes, Integrative analysis, POLYUNSATURATED FATTY-ACIDS, WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, GENETIC-FACTORS, CROHNS-DISEASE, EXPRESSION, COMMON, VARIANTS, RARE, SUSCEPTIBILITY",

author = "Xiaojing Chu and Martin Jaeger and Joep Beumer and Bakker, {Olivier B.} and Raul Aguirre-Gamboa and Marije Oosting and Smeekens, {Sanne P.} and Simone Moorlag and Mourits, {Vera P.} and Koeken, {Valerie A. C. M.} and {de Bree}, Charlotte and Trees Jansen and Mathews, {Ian T.} and Khoi Dao and Mahan Najhawan and Watrous, {Jeramie D.} and Irma Joosten and Sonia Sharma and Koenen, {Hans J. P. M.} and Sebo Withoff and Jonkers, {Iris H.} and Netea-Maier, {Romana T.} and Xavier, {Ramnik J.} and Lude Franke and Cheng-Jian Xu and Joosten, {Leo A. B.} and Serena Sanna and Mohit Jain and Vinod Kumar and Hans Clevers and Cisca Wijmenga and Netea, {Mihai G.} and Yang Li",

year = "2021",

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doi = "10.1186/s13059-021-02413-z",

language = "English",

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Chu, X, Jaeger, M, Beumer, J, Bakker, OB, Aguirre-Gamboa, R, Oosting, M, Smeekens, SP, Moorlag, S, Mourits, VP, Koeken, VACM, de Bree, C, Jansen, T, Mathews, IT, Dao, K, Najhawan, M, Watrous, JD, Joosten, I, Sharma, S, Koenen, HJPM, Withoff, S , Jonkers, IH, Netea-Maier, RT, Xavier, RJ, Franke, L, Xu, C-J, Joosten, LAB, Sanna, S, Jain, M, Kumar, V, Clevers, H, Wijmenga, C, Netea, MG & Li, Y 2021, 'Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease', Genome Biology, vol. 22, no. 1, 198. https://doi.org/10.1186/s13059-021-02413-z

TY - JOUR

T1 - Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

AU - Chu, Xiaojing

AU - Jaeger, Martin

AU - Beumer, Joep

AU - Bakker, Olivier B.

AU - Aguirre-Gamboa, Raul

AU - Oosting, Marije

AU - Smeekens, Sanne P.

AU - Moorlag, Simone

AU - Mourits, Vera P.

AU - Koeken, Valerie A. C. M.

AU - de Bree, Charlotte

AU - Jansen, Trees

AU - Mathews, Ian T.

AU - Dao, Khoi

AU - Najhawan, Mahan

AU - Watrous, Jeramie D.

AU - Joosten, Irma

AU - Sharma, Sonia

AU - Koenen, Hans J. P. M.

AU - Withoff, Sebo

AU - Jonkers, Iris H.

AU - Netea-Maier, Romana T.

AU - Xavier, Ramnik J.

AU - Franke, Lude

AU - Xu, Cheng-Jian

AU - Joosten, Leo A. B.

AU - Sanna, Serena

AU - Jain, Mohit

AU - Kumar, Vinod

AU - Clevers, Hans

AU - Wijmenga, Cisca

AU - Netea, Mihai G.

AU - Li, Yang

PY - 2021/7/6

Y1 - 2021/7/6

N2 - BACKGROUND: Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors.RESULT: We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target.CONCLUSION: This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.

AB - BACKGROUND: Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors.RESULT: We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn's disease, suggesting it is a potential therapeutic target.CONCLUSION: This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.

KW - Metabolomics

KW - Genomics

KW - Immune phenotypes

KW - Integrative analysis

KW - POLYUNSATURATED FATTY-ACIDS

KW - WIDE ASSOCIATION

KW - MENDELIAN RANDOMIZATION

KW - GENETIC-FACTORS

KW - CROHNS-DISEASE

KW - EXPRESSION

KW - COMMON

KW - VARIANTS

KW - RARE

KW - SUSCEPTIBILITY

U2 - 10.1186/s13059-021-02413-z

DO - 10.1186/s13059-021-02413-z

M3 - Article

C2 - 34229738

SN - 1465-6906

VL - 22

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 198

ER -

Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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Additional file 13 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Additional file 2 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

Additional file 9 of Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease

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