Proteome-wide Systems Genetics to Identify Functional Regulators of Complex Traits

Molendijk, Jeffrey; Parker, Benjamin L.

doi:10.1016/j.cels.2020.10.005

Cited by 20 publications

(19 citation statements)

References 194 publications

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“…Eventually, studying the complexity and effects of combining many different genetic variants will present exciting opportunities for proteomics to inform about cellular mechanisms on a molecular level. 141 This is exemplified by GWAS-anchored studies connecting multiomic signatures of mRNA expression and levels of circulating protein and metabolites. 142…”

Section: Quantitative Trait Locimentioning

confidence: 99%

“…In comparison with the affinity proteomics studies, there are currently not a substantial number of GWAS studies that are based on MS-derived plasma data. − Thus there is a huge potential of adding sequence-resolved MS-based proteomics data to these studies. Eventually, studying the complexity and effects of combining many different genetic variants will present exciting opportunities for proteomics to inform about cellular mechanisms on a molecular level . This is exemplified by GWAS-anchored studies connecting multiomic signatures of mRNA expression and levels of circulating protein and metabolites …”

Section: Proteomics Genomics and Protein Quantitative Trait Locimentioning

confidence: 99%

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Advances and Utility of the Human Plasma Proteome

et al. 2021

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The study of proteins circulating in blood offers tremendous opportunities to diagnose, stratify, or possibly prevent diseases. With recent technological advances and the urgent need to understand the effects of COVID-19, the proteomic analysis of blood-derived serum and plasma has become even more important for studying human biology and pathophysiology. Here we provide views and perspectives about technological developments and possible clinical applications that use mass-spectrometry(MS)- or affinity-based methods. We discuss examples where plasma proteomics contributed valuable insights into SARS-CoV-2 infections, aging, and hemostasis and the opportunities offered by combining proteomics with genetic data. As a contribution to the Human Proteome Organization (HUPO) Human Plasma Proteome Project (HPPP), we present the Human Plasma PeptideAtlas build 2021-07 that comprises 4395 canonical and 1482 additional nonredundant human proteins detected in 240 MS-based experiments. In addition, we report the new Human Extracellular Vesicle PeptideAtlas 2021-06, which comprises five studies and 2757 canonical proteins detected in extracellular vesicles circulating in blood, of which 74% (2047) are in common with the plasma PeptideAtlas. Our overview summarizes the recent advances, impactful applications, and ongoing challenges for translating plasma proteomics into utility for precision medicine.

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Section: Quantitative Trait Locimentioning

confidence: 99%

Section: Proteomics Genomics and Protein Quantitative Trait Locimentioning

confidence: 99%

Advances and Utility of the Human Plasma Proteome

et al. 2021

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“…In addition, understanding the relative detection sensitivity of each method will be essential for successfully quantifying the relationship between RNA and protein isoforms. Thanks to recent advances, integration of genomics, transcriptomics and proteomics to improve our understanding of traits and diseases is now feasible, opening up new opportunities to examine the role of RNA and protein isoforms in health and disease ( Molendijk and Parker, 2021 ).…”

Section: The Impact Of Alternative Splicing On Protein Function and Abundancementioning

confidence: 99%

Isoform Age - Splice Isoform Profiling Using Long-Read Technologies

Paoli-Iseppi

Gleeson

Clark

2021

Front. Mol. Biosci.

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Alternative splicing (AS) of RNA is a key mechanism that results in the expression of multiple transcript isoforms from single genes and leads to an increase in the complexity of both the transcriptome and proteome. Regulation of AS is critical for the correct functioning of many biological pathways, while disruption of AS can be directly pathogenic in diseases such as cancer or cause risk for complex disorders. Current short-read sequencing technologies achieve high read depth but are limited in their ability to resolve complex isoforms. In this review we examine how long-read sequencing (LRS) technologies can address this challenge by covering the entire RNA sequence in a single read and thereby distinguish isoform changes that could impact RNA regulation or protein function. Coupling LRS with technologies such as single cell sequencing, targeted sequencing and spatial transcriptomics is producing a rapidly expanding suite of technological approaches to profile alternative splicing at the isoform level with unprecedented detail. In addition, integrating LRS with genotype now allows the impact of genetic variation on isoform expression to be determined. Recent results demonstrate the potential of these techniques to elucidate the landscape of splicing, including in tissues such as the brain where AS is particularly prevalent. Finally, we also discuss how AS can impact protein function, potentially leading to novel therapeutic targets for a range of diseases.

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“…pQTLs refer to associations between genetic variants and protein abundance levels which can be cis-pQTLs or trans-pQTLs (Suhre et al, 2021). Cis-pQTLs specify variants that are likely to have a direct effect on the observed protein levels at that locus, whereas trans-pQTLs specify a variant distant to the protein-coding gene or on another chromosome that could indicate an indirect link (Molendijk and Parker, 2021).…”

Section: Integration With Genomic Datamentioning

confidence: 99%

Towards Building a Quantitative Proteomics Toolbox in Precision Medicine: A Mini-Review

et al. 2021

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Precision medicine as a framework for disease diagnosis, treatment, and prevention at the molecular level has entered clinical practice. From the start, genetics has been an indispensable tool to understand and stratify the biology of chronic and complex diseases in precision medicine. However, with the advances in biomedical and omics technologies, quantitative proteomics is emerging as a powerful technology complementing genetics. Quantitative proteomics provide insight about the dynamic behaviour of proteins as they represent intermediate phenotypes. They provide direct biological insights into physiological patterns, while genetics accounting for baseline characteristics. Additionally, it opens a wide range of applications in clinical diagnostics, treatment stratification, and drug discovery. In this mini-review, we discuss the current status of quantitative proteomics in precision medicine including the available technologies and common methods to analyze quantitative proteomics data. Furthermore, we highlight the current challenges to put quantitative proteomics into clinical settings and provide a perspective to integrate proteomics data with genomics data for future applications in precision medicine.

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Proteome-wide Systems Genetics to Identify Functional Regulators of Complex Traits

Cited by 20 publications

References 194 publications

Advances and Utility of the Human Plasma Proteome

Advances and Utility of the Human Plasma Proteome

Isoform Age - Splice Isoform Profiling Using Long-Read Technologies

Towards Building a Quantitative Proteomics Toolbox in Precision Medicine: A Mini-Review

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