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<p>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.</p>

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Plasma proteome variation and its genetic determinants in children and adolescents

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月19日

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  • 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

摘要

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.