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Updated: Sep 14, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Proteome-wide Mendelian randomization and colocalization analyses identify novel protein targets for cardiac
Zheng-Qi Song1, Yu-Peng Xu2, Yi-Qi Chen3
1Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou, Zhejiang, China; The First Clinical Medical College, Wenzhou Medical University, Chashan, Wenzhou, Zhejiang, China.
Insights
This study identifies novel protein targets for cardiac conduction disorder (CCD), including CASP9 and ASPH, offering new avenues for treatment. It also uncovers potential biological mechanisms, such as hyperkalemia, underlying CCD development.
Area of Science:
- Genetics
- Cardiology
- Pharmacology
Background:
- Cardiac conduction disorder (CCD) presents a significant health risk with limited treatment options.
- Current understanding of CCD mechanisms and therapeutic strategies is insufficient.
Purpose of the Study:
- To identify novel protein targets associated with cardiac conduction disorder (CCD).
- To elucidate the biological mechanisms underlying CCD development and progression.
Main Methods:
- Utilized protein quantitative trait loci from UKBPPP and deCODE Health study databases.
- Performed Mendelian randomization and colocalization analyses using FinnGen R11 data for genetic associations.
- Conducted Phenome-wide association study (PheWAS), multivariable Mendelian randomization (MVMR), and multi-omics analyses.
Main Results:
- Genetically predicted CASP9 and ASPH showed significant association with increased atrioventricular block risk.
- SRA1 was significantly associated with a lower risk of atrioventricular block.
- CFHR5 showed suggestive association with decreased left bundle branch block incidence; hyperkalemia identified as a potential mediator for CASP9.
Conclusions:
- Identified CASP9, ASPH, SRA1, and CFHR5 as novel protein targets for CCD.
- Uncovered potential biological pathways, including hyperkalemia and specific methylation sites, involved in CCD.
Background:
The occurrence and progression of cardiac conduction disorder (CCD) pose a significant threat to people's health. However, current pharmacological treatments for CCD are relatively limited, with few mechanistic studies and intervention strategies.
Methods:
We derived protein quantitative trait loci from two comprehensive databases: UKBPPP and deCODE Health study. Genetic associations with CCD and its subsets were obtained from the FinnGen R11 database. Summary-data-based Mendelian randomization and colocalization analyses were conducted to identify potential protein targets. Phenome-wide association study (PheWAS), multivariable Mendelian randomization (MVMR), and multi-omic analyses were further performed to elucidate the underlying biological mechanisms of the identified protein targets.
Results:
Genetically predicted CASP9 (OR: 2.65, 95 % CI: 1.65 to 4.26, pFDR = 0.007) and ASPH (OR: 2.03, 95 % CI: 1.32 to 3.11, pFDR = 0.024) were significantly associated with a higher risk of atrioventricular block, while genetically predicted SRA1 (OR: 0.54, 95 % CI: 0.39 to 0.75, pFDR = 0.009) was markedly associated with a lower risk of atrioventricular block. Additionally, the protein CFHR5 (OR: 0.82, 95 % CI: 0.70 to 0.96, pFDR = 0.157) was linked to a decreased incidence of left bundle branch block with suggestive significance. PheWAS and MVMR analyses suggested that hyperkalemia may serve as a potential mediating pathway between CASP9 and atrioventricular block. Multi-omics analysis revealed several methylation sites of CASP9 linked with atrioventricular block.
Conclusion:
We identified several novel protein targets for CCD and uncovered their underlying biological processes.
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