{"id":{"repo_id":"uic","oai_identifier":"oai:figshare.com:article/32991842"},"canonical_url":"https://search.dev.ndltd.org/etd/uic/oai:figshare.com:article/32991842","repository":{"repo_id":"uic","name":"University of Illinois - Chicago","base_url":"https://api.figshare.com/v2/oai"},"display":{"title":"Mechanism of Atrial Fibrillation in Lamin A/C Cardiomyopathy","abstract":"Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Polygenic risk score (PRS) assessment in the UK Biobank and All of Us cohorts shows that the risk of incident AF in carriers of protein-altering variants (PAV) in LMNA is significantly greater than predicted by a PRS alone, suggesting a synergistic interaction between common polymorphisms and LMNA variants. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant disrupts chromatin architecture, leading to the perturbation of atrial gene regulatory networks that involve regulatory regions harboring AF-associated variants and transcription factors crucial for atrial rhythm control and contractility. Using CRISPR epigenetic modifiers, we interrogate the function of several AF-associated regulatory regions and their target genes. Specifically, reduced accessibility at an SCN10A intronic enhancer harboring the AF-associated SNP, rs6801957, which is known to regulate sodium current, leads to reduced sodium current in LMNA-S143P iPSC-aCMs. In conclusion, we demonstrate how a LMNA variant and common polymorphisms disrupt shared gene regulatory networks underlying arrhythmia susceptibility, highlighting the need to integrate rare and common variants for more accurate assessment of AF risk.","abstract_html":"Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Polygenic risk score (PRS) assessment in the UK Biobank and All of Us cohorts shows that the risk of incident AF in carriers of protein-altering variants (PAV) in LMNA is significantly greater than predicted by a PRS alone, suggesting a synergistic interaction between common polymorphisms and LMNA variants. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant disrupts chromatin architecture, leading to the perturbation of atrial gene regulatory networks that involve regulatory regions harboring AF-associated variants and transcription factors crucial for atrial rhythm control and contractility. Using CRISPR epigenetic modifiers, we interrogate the function of several AF-associated regulatory regions and their target genes. Specifically, reduced accessibility at an SCN10A intronic enhancer harboring the AF-associated SNP, rs6801957, which is known to regulate sodium current, leads to reduced sodium current in LMNA-S143P iPSC-aCMs. In conclusion, we demonstrate how a LMNA variant and common polymorphisms disrupt shared gene regulatory networks underlying arrhythmia susceptibility, highlighting the need to integrate rare and common variants for more accurate assessment of AF risk.","abstract_has_math":false,"creators":["Asia Owais (21248177)"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026-07-15T12:00:15Z","date_published":"2026-07-15T12:00:15Z","updated_at":"2026-07-27T21:33:07Z","subjects":["Arrhythmia + Cardiomyopathy + Genetics"],"languages":[],"rights":["In Copyright"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.25417/uic.32991842.v1","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Asia Owais (21248177)"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2026-07-15T12:00:15Z"]},{"key":"dc:relation","label":"Dc Relation","values":["https://figshare.com/articles/thesis/Mechanism_of_Atrial_Fibrillation_in_Lamin_A_C_Cardiomyopathy/32991842"]},{"key":"dc:type","label":"Dc Type","values":["Text","Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Arrhythmia + Cardiomyopathy + Genetics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["10.25417/uic.32991842.v1"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Polygenic risk score (PRS) assessment in the UK Biobank and All of Us cohorts shows that the risk of incident AF in carriers of protein-altering variants (PAV) in LMNA is significantly greater than predicted by a PRS alone, suggesting a synergistic interaction between common polymorphisms and LMNA variants. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant disrupts chromatin architecture, leading to the perturbation of atrial gene regulatory networks that involve regulatory regions harboring AF-associated variants and transcription factors crucial for atrial rhythm control and contractility. Using CRISPR epigenetic modifiers, we interrogate the function of several AF-associated regulatory regions and their target genes. Specifically, reduced accessibility at an SCN10A intronic enhancer harboring the AF-associated SNP, rs6801957, which is known to regulate sodium current, leads to reduced sodium current in LMNA-S143P iPSC-aCMs. In conclusion, we demonstrate how a LMNA variant and common polymorphisms disrupt shared gene regulatory networks underlying arrhythmia susceptibility, highlighting the need to integrate rare and common variants for more accurate assessment of AF risk."]},{"key":"dc:title","label":"Title","values":["Mechanism of Atrial Fibrillation in Lamin A/C Cardiomyopathy"]}]}],"canonical_facts":{"dc:creator":["Asia Owais (21248177)"],"dc:date":["2026-07-15T12:00:15Z"],"dc:description":["Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Polygenic risk score (PRS) assessment in the UK Biobank and All of Us cohorts shows that the risk of incident AF in carriers of protein-altering variants (PAV) in LMNA is significantly greater than predicted by a PRS alone, suggesting a synergistic interaction between common polymorphisms and LMNA variants. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant disrupts chromatin architecture, leading to the perturbation of atrial gene regulatory networks that involve regulatory regions harboring AF-associated variants and transcription factors crucial for atrial rhythm control and contractility. Using CRISPR epigenetic modifiers, we interrogate the function of several AF-associated regulatory regions and their target genes. Specifically, reduced accessibility at an SCN10A intronic enhancer harboring the AF-associated SNP, rs6801957, which is known to regulate sodium current, leads to reduced sodium current in LMNA-S143P iPSC-aCMs. In conclusion, we demonstrate how a LMNA variant and common polymorphisms disrupt shared gene regulatory networks underlying arrhythmia susceptibility, highlighting the need to integrate rare and common variants for more accurate assessment of AF risk."],"dc:identifier":["10.25417/uic.32991842.v1"],"dc:relation":["https://figshare.com/articles/thesis/Mechanism_of_Atrial_Fibrillation_in_Lamin_A_C_Cardiomyopathy/32991842"],"dc:rights":["In Copyright"],"dc:subject":["Arrhythmia + Cardiomyopathy + Genetics"],"dc:title":["Mechanism of Atrial Fibrillation in Lamin A/C Cardiomyopathy"],"dc:type":["Text","Thesis"]},"updated_at":"2026-07-27T21:33:07Z"}