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Cited by 7Genetic Associations and EpidemiologyBioinformatics and Genomic NetworksCerebrovascular and genetic disorders

Identification of pleiotropic and specific therapeutic targets for cardio-cerebral diseases: A large-scale proteome-wide mendelian randomization and colocalization study

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Zhu, Yanchen, Wang, Yahui, Cui, Zhaorui, Liu, Fani, Hu, Jiqiang·2024·PLOS ONE
DOI 10.1371/journal.pone.0300500PMC PMC11142593
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Abstract

Background: The cardiac-brain connection has been identified as the basis for multiple cardio-cerebral diseases. However, effective therapeutic targets for these diseases are still limited. Therefore, this study aimed to identify pleiotropic and specific therapeutic targets for cardio-cerebral diseases using Mendelian randomization (MR) and colocalization analyses. Methods: This study included two large protein quantitative trait loci studies with over 4,000 plasma proteins were included in the discovery and replication cohorts, respectively. We initially used MR to estimate the associations between protein and 20 cardio-cerebral diseases. Subsequently, Colocalization analysis was employed to enhance the credibility of the results. Protein target prioritization was based solely on including highly robust significant results from both the discovery and replication phases. Lastly, the Drug-Gene Interaction Database was utilized to investigate protein-gene-drug interactions further. Results: A total of 46 target proteins for cardio-cerebral diseases were identified as robust in the discovery and replication phases by MR, comprising 7 pleiotropic therapeutic proteins and 39 specific target proteins. Followed by colocalization analysis and prioritization of evidence grades for target protein, 6 of these protein-disease pairs have achieved the highly recommended level. For instance, the PILRA protein presents a pleiotropic effect on sick sinus syndrome and Alzheimer’s disease, whereas GRN exerts specific effects on the latter. APOL3, LRP4, and F11, on the other hand, have specific effects on cardiomyopathy and ischemic stroke, respectively. Conclusions: This study successfully identified important therapeutic targets for cardio-cerebral diseases, which benefits the development of preventive or therapeutic drugs.

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  • The PILRA protein has been linked to Alzheimer's Disease (AD) in multiple MR studies using Olink pQTL instruments, but different directions of effect for PILRA on AD have been reported across studies using different platform's pQTL instruments.

    “The PILRA protein discussed above has been linked to Alzheimer’s Disease (AD) in multiple MR studies using Olink pQTL instruments27–29; however, different directions of effect for PILRA on AD have been reported across studies using different platform’s pQTL instruments.”

    From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [29]

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Cited by

Sorted by citations

Authors
Zhu, Y., Wang, Y., Cui, Z., Liu, F., & Hu, J.
Affiliations
Beijing University of Chinese Medicine (CN)
Corresponding author
Hu, Jiqiang
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2024-05-31
Volume
19
Issue
5
Pages
e0300500
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0300500
PMC
PMC11142593
OpenAlex
W4399204269
Cited by
7
References
3
Citations by year
2026: 2 · 2025: 3 · 2024: 2
FWCI
1.85
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
the Capital’s Funds for Health Improvement and Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
Keywords
drug target identification, protein quantitative trait loci, plasma proteins, sick sinus syndrome, Alzheimer's disease, cardiomyopathy, ischemic stroke, gene regulatory networks, LRP4, F11
MeSH terms
Cardiovascular Diseases, Cerebrovascular Disorders, Humans, Proteome, Quantitative Trait Loci, Genome-Wide Association Study, Mendelian Randomization Analysis, Genetic Pleiotropy

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