Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system
Abstract Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the ident...
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2025-01-01
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| author | Shikha Vashisht Costantino Parisi Cecilia L. Winata |
| author_facet | Shikha Vashisht Costantino Parisi Cecilia L. Winata |
| author_sort | Shikha Vashisht |
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| description | Abstract Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the identification of a comprehensive set of single-nucleotide polymorphisms (SNPs). Notably, 90–95% of these variants reside in the noncoding genome, complicating the understanding of their underlying mechanisms. Here, we developed a systematic computational pipeline for the identification and analysis of CHD-associated SNPs spanning both coding and noncoding regions of the genome. Initially, we curated a thorough dataset of SNPs from GWAS-catalog and ClinVar database and filtered them based on CHD-related traits. Subsequently, these CHD-SNPs were annotated and categorized into noncoding and coding regions based on their location. To study the functional implications of noncoding CHD-SNPs, we cross-validated them with enhancer-specific histone modification marks from developing human heart across 9 Carnegie stages and identified potential cardiac enhancers. This approach led to the identification of 2,056 CHD-associated putative enhancers (CHD-enhancers), 38.9% of them overlapping with known enhancers catalogued in human enhancer disease database. We identified heart-related transcription factor binding sites within these CHD-enhancers, offering insights into the impact of SNPs on TF binding. Conservation analysis further revealed that many of these CHD-enhancers were highly conserved across vertebrates, suggesting their evolutionary significance. Utilizing heart-specific expression quantitative trait loci data, we further identified a subset of 63 CHD-SNPs with regulatory potential distributed across various cardiac tissues. Concurrently, coding CHD-SNPs were represented as a protein interaction network and its subsequent binding energy analysis focused on a pair of proteins within this network, pinpointed a deleterious coding CHD-SNP, rs770030288, located in C2 domain of MYBPC3 protein. Overall, our findings demonstrate that SNPs have the potential to disrupt gene regulatory systems, either by affecting enhancer sequences or modulating protein-protein interactions, which can lead to abnormal developmental processes contributing to CHD pathogenesis. |
| format | Article |
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| institution | Kabale University |
| issn | 1471-2164 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | BMC Genomics |
| spelling | doaj-art-37166f3175274b8990d6c061c5252edf2025-01-26T12:16:34ZengBMCBMC Genomics1471-21642025-01-0126111710.1186/s12864-025-11232-6Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory systemShikha Vashisht0Costantino Parisi1Cecilia L. Winata2International Institute of Molecular and Cell Biology in Warsaw, Laboratory of Zebrafish Developmental GenomicsInternational Institute of Molecular and Cell Biology in Warsaw, Laboratory of Zebrafish Developmental GenomicsInternational Institute of Molecular and Cell Biology in Warsaw, Laboratory of Zebrafish Developmental GenomicsAbstract Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the identification of a comprehensive set of single-nucleotide polymorphisms (SNPs). Notably, 90–95% of these variants reside in the noncoding genome, complicating the understanding of their underlying mechanisms. Here, we developed a systematic computational pipeline for the identification and analysis of CHD-associated SNPs spanning both coding and noncoding regions of the genome. Initially, we curated a thorough dataset of SNPs from GWAS-catalog and ClinVar database and filtered them based on CHD-related traits. Subsequently, these CHD-SNPs were annotated and categorized into noncoding and coding regions based on their location. To study the functional implications of noncoding CHD-SNPs, we cross-validated them with enhancer-specific histone modification marks from developing human heart across 9 Carnegie stages and identified potential cardiac enhancers. This approach led to the identification of 2,056 CHD-associated putative enhancers (CHD-enhancers), 38.9% of them overlapping with known enhancers catalogued in human enhancer disease database. We identified heart-related transcription factor binding sites within these CHD-enhancers, offering insights into the impact of SNPs on TF binding. Conservation analysis further revealed that many of these CHD-enhancers were highly conserved across vertebrates, suggesting their evolutionary significance. Utilizing heart-specific expression quantitative trait loci data, we further identified a subset of 63 CHD-SNPs with regulatory potential distributed across various cardiac tissues. Concurrently, coding CHD-SNPs were represented as a protein interaction network and its subsequent binding energy analysis focused on a pair of proteins within this network, pinpointed a deleterious coding CHD-SNP, rs770030288, located in C2 domain of MYBPC3 protein. Overall, our findings demonstrate that SNPs have the potential to disrupt gene regulatory systems, either by affecting enhancer sequences or modulating protein-protein interactions, which can lead to abnormal developmental processes contributing to CHD pathogenesis.https://doi.org/10.1186/s12864-025-11232-6Congenital heart diseaseSingle-nucleotide polymorphismEnhancerProtein-protein interaction networkGene regulatory system |
| spellingShingle | Shikha Vashisht Costantino Parisi Cecilia L. Winata Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system BMC Genomics Congenital heart disease Single-nucleotide polymorphism Enhancer Protein-protein interaction network Gene regulatory system |
| title | Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system |
| title_full | Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system |
| title_fullStr | Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system |
| title_full_unstemmed | Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system |
| title_short | Computational analysis of congenital heart disease associated SNPs: unveiling their impact on the gene regulatory system |
| title_sort | computational analysis of congenital heart disease associated snps unveiling their impact on the gene regulatory system |
| topic | Congenital heart disease Single-nucleotide polymorphism Enhancer Protein-protein interaction network Gene regulatory system |
| url | https://doi.org/10.1186/s12864-025-11232-6 |
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