Plasma proteome variation and its genetic determinants in children and adolescents

Lili Niu; Sara Elizabeth Stinson; Louise Aas Holm; Morten Asp Vonsild Lund; Cilius Esmann Fonvig; Leonardo Cobuccio; Jonas Meisner; Helene Bæk Juel; Joao Fadista; Maja Thiele; Aleksander Krag; Jens Christian Holm; Simon Rasmussen; Torben Hansen; Matthias Mann

doi:10.1038/s41588-025-02089-2

Plasma proteome variation and its genetic determinants in children and adolescents

Lili Niu, Sara Elizabeth Stinson, Louise Aas Holm, Morten Asp Vonsild Lund, Cilius Esmann Fonvig, Leonardo Cobuccio, Jonas Meisner, Helene Bæk Juel, Joao Fadista, Maja Thiele, Aleksander Krag, Jens Christian Holm, Simon Rasmussen^*, Torben Hansen^*, Matthias Mann^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

1 Citation (Scopus)

Abstract

Our current understanding of the determinants of plasma proteome variation during pediatric development remains incomplete. Here, we show that genetic variants, age, sex and body mass index significantly influence this variation. Using a streamlined and highly quantitative mass spectrometry-based proteomics workflow, we analyzed plasma from 2,147 children and adolescents, identifying 1,216 proteins after quality control. Notably, the levels of 70% of these were associated with at least one of the aforementioned factors, with protein levels also being predictive. Quantitative trait loci (QTLs) regulated at least one-third of the proteins; between a few percent and up to 30-fold. Together with excellent replication in an additional 1,000 children and 558 adults, this reveals substantial genetic effects on plasma protein levels, persisting from childhood into adulthood. Through Mendelian randomization and colocalization analyses, we identified 41 causal genes for 33 cardiometabolic traits, emphasizing the value of protein QTLs in drug target identification and disease understanding.

Original language	English
Article number	e2000038
Journal	Nature Genetics
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-025-02089-2
Publication status	Accepted/In press - 2025

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Publisher Copyright:
© The Author(s) 2025.

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10.1038/s41588-025-02089-2

Cite this

Niu, L., Stinson, S. E., Holm, L. A., Lund, M. A. V., Fonvig, C. E., Cobuccio, L., Meisner, J., Juel, H. B., Fadista, J., Thiele, M., Krag, A., Holm, J. C., Rasmussen, S., Hansen, T., & Mann, M. (Accepted/In press). Plasma proteome variation and its genetic determinants in children and adolescents. Nature Genetics, Article e2000038. https://doi.org/10.1038/s41588-025-02089-2

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title = "Plasma proteome variation and its genetic determinants in children and adolescents",

abstract = "Our current understanding of the determinants of plasma proteome variation during pediatric development remains incomplete. Here, we show that genetic variants, age, sex and body mass index significantly influence this variation. Using a streamlined and highly quantitative mass spectrometry-based proteomics workflow, we analyzed plasma from 2,147 children and adolescents, identifying 1,216 proteins after quality control. Notably, the levels of 70% of these were associated with at least one of the aforementioned factors, with protein levels also being predictive. Quantitative trait loci (QTLs) regulated at least one-third of the proteins; between a few percent and up to 30-fold. Together with excellent replication in an additional 1,000 children and 558 adults, this reveals substantial genetic effects on plasma protein levels, persisting from childhood into adulthood. Through Mendelian randomization and colocalization analyses, we identified 41 causal genes for 33 cardiometabolic traits, emphasizing the value of protein QTLs in drug target identification and disease understanding.",

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AU - Niu, Lili

AU - Stinson, Sara Elizabeth

AU - Holm, Louise Aas

AU - Lund, Morten Asp Vonsild

AU - Fonvig, Cilius Esmann

AU - Cobuccio, Leonardo

AU - Meisner, Jonas

AU - Juel, Helene Bæk

AU - Fadista, Joao

AU - Thiele, Maja

AU - Krag, Aleksander

AU - Holm, Jens Christian

AU - Rasmussen, Simon

AU - Hansen, Torben

AU - Mann, Matthias

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AB - Our current understanding of the determinants of plasma proteome variation during pediatric development remains incomplete. Here, we show that genetic variants, age, sex and body mass index significantly influence this variation. Using a streamlined and highly quantitative mass spectrometry-based proteomics workflow, we analyzed plasma from 2,147 children and adolescents, identifying 1,216 proteins after quality control. Notably, the levels of 70% of these were associated with at least one of the aforementioned factors, with protein levels also being predictive. Quantitative trait loci (QTLs) regulated at least one-third of the proteins; between a few percent and up to 30-fold. Together with excellent replication in an additional 1,000 children and 558 adults, this reveals substantial genetic effects on plasma protein levels, persisting from childhood into adulthood. Through Mendelian randomization and colocalization analyses, we identified 41 causal genes for 33 cardiometabolic traits, emphasizing the value of protein QTLs in drug target identification and disease understanding.

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