{"doi":"10.64898/2025.12.02.691900","title":"Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants","abstract":"<jats:title>Abstract (Summary)</jats:title>\n                <jats:p>Genome-wide association studies (GWAS) have mapped thousands of congenital heart disease (CHD)-associated variants within non-coding regions of the genome. Non-coding variants can alter regulatory mechanisms, such as transcription factor (TF) binding control of gene expression, potentially contributing human diseases. However, with the increasing number of disease-associated variants, comprehensive functional validation remains a significant challenge. In this work, we developed a novel method called SNP Bind-n-Seq to evaluate &gt;3,000 CHD-risk variants for allelic binding for the cardiac TFs NKX2-5, GATA4, and TBX5 in a high-throughput manner. These binding affinity data sets were coupled with a massively parallel reporter assay (MPRA) to screen CHD-risk variant genotype-dependent regulatory activity. We identified 170 variants that exhibit allelic TF binding and 187 that modulate gene expression. Combining both approaches revealed three high-confidence variants with genotype-dependent TF binding, genotype-dependent transcriptional activity, and eQTL behavior in cardiac cells. Collectively, this study provides the first combined high-throughput biochemical and functional genomic evaluation of thousands of CHD-risk variants.</jats:p>\n                <jats:sec>\n                  <jats:title>Highlights:</jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Allelic binding affinity measurements of ∼9,600 variants for NKX2-5, GATA4, and TBX5</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>EvaluaFon of &gt;3,000 CHD-risk variants for genotype-dependent regulatory acFvity</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>InteracFon networks idenFfy funcFonal variants and genes involving cardiac eQTLs</jats:p>\n                    </jats:list-item>\n                  </jats:list>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract</jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"691900v2_ufig1\" position=\"float\" orientation=\"portrait\"/>\n                  </jats:fig>\n                </jats:sec>","journal":null,"year":null,"id":631872,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1637638,"name":"Shreya Sharma","orcid":null,"position":1,"is_corresponding":false},{"id":574733,"name":"Joshua G. Medina-Feliciano","orcid":"0000-0001-5678-3495","position":2,"is_corresponding":false},{"id":1155052,"name":"Elise Root","orcid":"0009-0000-8158-6442","position":3,"is_corresponding":false},{"id":783818,"name":"Lois Parks","orcid":"0000-0001-5689-7492","position":4,"is_corresponding":false},{"id":932785,"name":"Marissa Granitto","orcid":"0000-0002-1758-9881","position":5,"is_corresponding":false},{"id":1002385,"name":"Diego A. Pomales‐Matos","orcid":"0000-0002-4129-7678","position":6,"is_corresponding":false},{"id":1119889,"name":"Jean L. Messon-Bird","orcid":"0009-0000-3276-1902","position":7,"is_corresponding":false},{"id":1119890,"name":"Adriana C. Barreiro-Rosario","orcid":"0000-0002-0662-3650","position":8,"is_corresponding":false},{"id":1011782,"name":"Leandro Sanabria-Alberto","orcid":"0009-0004-8203-4139","position":9,"is_corresponding":false},{"id":1011781,"name":"Alejandro Rivera-Madera","orcid":"0000-0003-0037-4822","position":10,"is_corresponding":false},{"id":826964,"name":"Jessica M. Rodríguez-Ríos","orcid":"0000-0001-9845-9642","position":11,"is_corresponding":false},{"id":1425620,"name":"Rosalba Velázquez-Roig","orcid":"0000-0001-8480-8856","position":12,"is_corresponding":false},{"id":1426006,"name":"Juan A. Figueroa-Rosado","orcid":null,"position":13,"is_corresponding":false},{"id":632256,"name":"Mackenzie Noon","orcid":"0000-0002-7531-5280","position":14,"is_corresponding":false},{"id":301417,"name":"Rebekah Karns","orcid":"0000-0002-9720-4039","position":15,"is_corresponding":false},{"id":580584,"name":"Carmy Forney","orcid":"0000-0001-6418-5794","position":16,"is_corresponding":false},{"id":1333021,"name":"Hayley K. Hesse","orcid":null,"position":17,"is_corresponding":false},{"id":1333023,"name":"Katelyn A. Dunn","orcid":null,"position":18,"is_corresponding":false},{"id":229081,"name":"Xiaoting Chen","orcid":"0000-0002-3782-3962","position":19,"is_corresponding":false},{"id":340127,"name":"Matthew R. Hass","orcid":"0000-0001-9507-4333","position":20,"is_corresponding":false},{"id":1220438,"name":"Lucinda P. Lawson","orcid":"0000-0003-3939-7829","position":21,"is_corresponding":false},{"id":19923,"name":"Matthew T. Weirauch","orcid":"0000-0001-7977-9122","position":22,"is_corresponding":false},{"id":250976,"name":"Leah C. Kottyan","orcid":"0000-0003-3979-2220","position":23,"is_corresponding":false},{"id":3036,"name":"Steven K. Reilly","orcid":"0000-0003-3140-1483","position":24,"is_corresponding":false},{"id":434431,"name":"Devesh Bhimsaria","orcid":"0000-0001-8413-3801","position":25,"is_corresponding":false},{"id":826965,"name":"José A. Rodríguez‐Martínez","orcid":"0000-0002-1191-2887","position":26,"is_corresponding":false},{"id":1011780,"name":"Edwin G. Peña-Martínez","orcid":"0000-0002-9076-528X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants","abstract":"<jats:title>Abstract (Summary)</jats:title>\n                <jats:p>Genome-wide association studies (GWAS) have mapped thousands of congenital heart disease (CHD)-associated variants within non-coding regions of the genome. Non-coding variants can alter regulatory mechanisms, such as transcription factor (TF) binding control of gene expression, potentially contributing human diseases. However, with the increasing number of disease-associated variants, comprehensive functional validation remains a significant challenge. In this work, we developed a novel method called SNP Bind-n-Seq to evaluate &gt;3,000 CHD-risk variants for allelic binding for the cardiac TFs NKX2-5, GATA4, and TBX5 in a high-throughput manner. These binding affinity data sets were coupled with a massively parallel reporter assay (MPRA) to screen CHD-risk variant genotype-dependent regulatory activity. We identified 170 variants that exhibit allelic TF binding and 187 that modulate gene expression. Combining both approaches revealed three high-confidence variants with genotype-dependent TF binding, genotype-dependent transcriptional activity, and eQTL behavior in cardiac cells. Collectively, this study provides the first combined high-throughput biochemical and functional genomic evaluation of thousands of CHD-risk variants.</jats:p>\n                <jats:sec>\n                  <jats:title>Highlights:</jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Allelic binding affinity measurements of ∼9,600 variants for NKX2-5, GATA4, and TBX5</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>EvaluaFon of &gt;3,000 CHD-risk variants for genotype-dependent regulatory acFvity</jats:p>\n                    </jats:list-item>\n                    <jats:list-item>\n                      <jats:p>InteracFon networks idenFfy funcFonal variants and genes involving cardiac eQTLs</jats:p>\n                    </jats:list-item>\n                  </jats:list>\n                </jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract</jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"691900v2_ufig1\" position=\"float\" orientation=\"portrait\"/>\n                  </jats:fig>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W4417117040","authors":[],"funders":[{"funder_name":"NIH","grant_id":"SC1GM127231","title":null},{"funder_name":"NIH","grant_id":"P20GM103475W","title":null},{"funder_name":"NIH","grant_id":"5R25GM061151–20","title":null},{"funder_name":"NIH","grant_id":"1T34GM145404","title":null},{"funder_name":"NIH","grant_id":"1R25HG012702–01","title":null},{"funder_name":"NIH","grant_id":"R01NS099068","title":null},{"funder_name":"NSF","grant_id":"1736026","title":null},{"funder_name":"NSF","grant_id":"HRD-2008186","title":null},{"funder_name":"NSF","grant_id":"1852259","title":null},{"funder_name":"NSF","grant_id":"STC-1231306","title":null},{"funder_name":"NSF","grant_id":"2050493","title":null},{"funder_name":"NSF","grant_id":"1744619","title":null},{"funder_name":"NIH","grant_id":"R01AI024717","title":null},{"funder_name":"NIH","grant_id":"R01AI148276","title":null},{"funder_name":"NIH","grant_id":"U24 HG013078","title":null},{"funder_name":"NIH","grant_id":"U01 HG011172","title":null},{"funder_name":"NIH","grant_id":"P30AR070549","title":null},{"funder_name":"NIH","grant_id":"R01HG012872","title":null}],"total_grants":18,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.64898/2025.12.02.691900","host_type":"repository"},{"url":"https://doi.org/10.64898/2025.12.02.691900","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.64898/2025.12.02.691900","host_type":"publisher"}],"fields_of_study":["Congenital heart defects research","Genetic Associations and Epidemiology","Genomics and Rare Diseases"],"mesh_terms":[],"keywords":["Transcription factor","Gene","Allele","Human genetics","SNP","Regulatory sequence","Genetic variants","Enhancer","Expression quantitative trait loci"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T00:56:45.755019Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}