In vivo identification and validation of novel potential predictors for human cardiovascular diseases

Genetics crucially contributes to cardiovascular diseases (CVDs), the global leading cause of death. Since the majority of CVDs can be prevented by early intervention there is a high demand for the identification of predictive causative genes. While genome wide association studies (GWAS) correlate g...

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Bibliographic Details
Published in:PloS one 2021-12, Vol.16 (12), p.e0261572-e0261572
Main Authors: Hammouda, Omar T, Wu, Meng Yue, Kaul, Verena, Gierten, Jakob, Thumberger, Thomas, Wittbrodt, Joachim
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified
Automation
Biological markers
Biology and Life Sciences
Cardiovascular diseases
Cardiovascular Diseases - diagnosis
Cardiovascular Diseases - genetics
Cardiovascular Diseases - pathology
Conservation
CRISPR
CRISPR-Cas Systems - genetics
Diagnosis
Embryos
Gene Editing
Genes
Genetic aspects
Genetic engineering
Genetics
Genome editing
Genome-wide association studies
Genome-Wide Association Study
Genomes
Heart function
Heart rate
Heart Rate - genetics
Humans
Localization
Medicine and Health Sciences
Myosin Light Chains - genetics
Oryzias - genetics
Phenotypes
Pipelines
Promoter Regions, Genetic - genetics
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Summary:Genetics crucially contributes to cardiovascular diseases (CVDs), the global leading cause of death. Since the majority of CVDs can be prevented by early intervention there is a high demand for the identification of predictive causative genes. While genome wide association studies (GWAS) correlate genes and CVDs after diagnosis and provide a valuable resource for such causative candidate genes, often preferentially those with previously known or suspected function are addressed further. To tackle the unaddressed blind spot of understudied genes, we particularly focused on the validation of human heart phenotype-associated GWAS candidates with little or no apparent connection to cardiac function. Building on the conservation of basic heart function and underlying genetics from fish to human we combined CRISPR/Cas9 genome editing of the orthologs of human GWAS candidates in isogenic medaka with automated high-throughput heart rate analysis. Our functional analyses of understudied human candidates uncovered a prominent fraction of heart rate associated genes from adult human patients impacting on the heart rate in embryonic medaka already in the injected generation. Following this pipeline, we identified 16 GWAS candidates with potential diagnostic and predictive power for human CVDs.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0261572