0/ Despite advances in plasma proteomics, our understanding of plasma proteome variation and its determinants during pediatric development remains incomplete.
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1/ Leveraging the recently introduced Orbitrap-Astral mass spectrometer, we measured the plasma proteomes of >3,000 individuals aged 5-20 in the HOLBAEK Study, quantifying >1,000 proteins per sample at 60 SPD throughput.
2/ We used multiple linear regression to assess the impact of age, sex, and BMI-SDS on the plasma proteome, finding 58% of the proteins associated with at least one factor according to the data and our modeling. Plasma proteins in turn also predicted age and BMI.
3/ We highlight intriguing protein abundance trajectories through puberty, including sex hormone-related differences and key bone development proteins linked to growth plate closure during skeletal maturation, reflecting the sex differences in onset of puberty.
4/ We tested 5.2 million SNPs for effects on plasma protein levels, leveraging peptide-level information to classify pQTLs by confidence and remove “epitope effect” artifacts. We also examined how technical factors such as CV and protein properties influence pQTL detection.
5/ Plasma protein levels are influenced by various factors, but the degree varies from protein to protein. Through variance decomposition we found that some proteins are mainly influenced by genetic variants, while others are shaped by factors like age and obesity.
6/ Using identified cis-pQTLs as genetic instruments, we performed systematic Mendelian randomization and colocalization analyses, identifying candidate causal genes for cardiometabolic traits across five therapy areas.
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