Unlocking the Human Proteome: Advancements in Brain, CSF, and Plasma with TOPMed Imputed Genomics
In the ever-evolving quest to unravel the complexities of the human body, a team of renowned scientists has made a remarkable stride, shedding light on the genetic underpinnings of protein regulation across multiple tissues. This comprehensive study, leveraging the power of the TOPMED imputed genomics, has significantly enhanced our understanding of the genetic control of the human proteome in brain, cerebrospinal fluid (CSF), and plasma.
The researchers, building upon their previous work, have now analyzed a staggering 1,300 proteins in brain, 869 proteins in CSF, and 953 proteins in plasma, a substantial increase from their earlier study. By harnessing the improved TOPMED reference panel, they were able to impute a remarkable 8.4 million high-quality genetic variants, nearly doubling the number of variants examined in their previous investigation.
The findings are truly remarkable. In brain, the team identified 38 genomic regions associated with 43 proteins, including 12 newly discovered loci. In CSF, they uncovered an astounding 150 genomic regions linked to 247 proteins, with 30 brand-new loci. And in plasma, they revealed 95 regions associated with 145 proteins, 22 of which were previously unidentified.
But the story doesn't end there. The researchers delved deeper, meticulously disentangling the independent signals within each locus, unveiling the intricate genetic architecture underlying protein regulation. In CSF alone, they found an astonishing 47 loci with more than one independent signal, showcasing the remarkable complexity of the human proteome.
Intriguingly, the team also identified numerous pleiotropic loci – genetic regions associated with multiple proteins – underscoring the intricate web of genetic regulation. The APOE locus on chromosome 19, for instance, was linked to an impressive 15 proteins in CSF, while the major histocompatibility complex (MHC) locus on chromosome 6 was associated with 16 proteins in plasma.
As a testament to the study's clinical significance, the researchers delved into the potential causal relationship between the identified proteins and Alzheimer's disease (AD). Employing Mendelian randomization and Bayesian colocalization analyses, they uncovered evidence of causality for several proteins, including the intriguing case of Cathepsin H. This protease, found to be causally linked to AD risk in all three tissues, serves as a prime example of how this groundbreaking work can uncover critical molecular pathways underlying complex neurological disorders.
To ensure the broader scientific community can benefit from these invaluable insights, the researchers have meticulously curated their findings and made them accessible through the Online Neurodegenerative Trait Integrative Multi-Omics Explorer (ONTIME) web portal. This interactive platform allows researchers to explore the intricate relationships between genetic variants, protein levels, and disease associations, paving the way for future breakthroughs in the field of neuroscience and beyond.
In the ever-evolving world of genomics and proteomics, this study stands as a beacon of hope, showcasing the power of integrative multi-omics approaches to unravel the intricate mysteries of the human body. By harnessing the latest advancements in imputation and bioinformatics, the research team has delivered a groundbreaking resource that promises to revolutionize our understanding of the genetic control of the human proteome, ultimately paving the way for novel therapeutic strategies and personalized healthcare solutions.
Source: https://www.nature.com/articles/s41597-024-03140-3
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