{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:43:37Z","timestamp":1790516617787,"version":"4.1.0"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL1351291"],"award-info":[{"award-number":["R01HL1351291"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM118557"],"award-info":[{"award-number":["R01GM118557"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["1U01HL137181"],"award-info":[{"award-number":["1U01HL137181"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) &gt;0.5% were evaluated.<\/jats:p>\n                    <jats:p>\n                      We identified novel loci near\n                      <jats:italic>LINC01021<\/jats:italic>\n                      ,\n                      <jats:italic>ATOH8<\/jats:italic>\n                      and\n                      <jats:italic>JAK2<\/jats:italic>\n                      genes that achieved genome-wide significance for AAA (p-value &lt;5x10\n                      <jats:sup>-8<\/jats:sup>\n                      ), in addition to three known loci. For TAA, three novel loci in\n                      <jats:italic>CTNNA3<\/jats:italic>\n                      ,\n                      <jats:italic>FRMD6<\/jats:italic>\n                      and\n                      <jats:italic>MBP<\/jats:italic>\n                      achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs ~10%) encompassing\n                      <jats:italic>FBN1<\/jats:italic>\n                      , the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this\n                      <jats:italic>FBN1<\/jats:italic>\n                      haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including\n                      <jats:italic>JAK2<\/jats:italic>\n                      association, offer plausible mechanistic and therapeutic insights. We also found a common\n                      <jats:italic>FBN1<\/jats:italic>\n                      linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These\n                      <jats:italic>FBN1<\/jats:italic>\n                      variants suggest shared pathophysiology between Marfan disease and sporadic TAA.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0247287","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T13:28:24Z","timestamp":1630502904000},"page":"e0247287","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":34,"title":["Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort"],"prefix":"10.1371","volume":"16","author":[{"given":"Tamara","family":"Ashvetiya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry X.","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ju","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles H.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery R.","family":"O\u2019Connell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5050-2074","authenticated-orcid":true,"given":"James A.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0424-8252","authenticated-orcid":true,"given":"Charles C.","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,1]]},"reference":[{"key":"pone.0247287.ref001","unstructured":"CDC. Aortic Aneurysm | cdc.gov. Centers for Disease Control and Prevention 2020. https:\/\/www.cdc.gov\/heartdisease\/aortic_aneurysm.htm. Accessed October 3, 2020."},{"key":"pone.0247287.ref002","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1161\/01.CIR.0000127857.77161.A1","article-title":"Genome scan for familial abdominal aortic aneurysm using sex and family history as covariates suggests genetic heterogeneity and identifies linkage to chromosome 19q13","volume":"109","author":"H Shibamura","year":"2004","journal-title":"Circulation"},{"key":"pone.0247287.ref003","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1161\/01.CIR.103.20.2461","article-title":"Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14","volume":"103","author":"D Guo","year":"2001","journal-title":"Circulation"},{"key":"pone.0247287.ref004","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1161\/01.CIR.103.20.2469","article-title":"Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder","volume":"103","author":"CJ Vaughan","year":"2001","journal-title":"Circulation"},{"key":"pone.0247287.ref005","doi-asserted-by":"crossref","DOI":"10.3390\/biom10020182","article-title":"The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective","volume":"10","author":"NP Ostberg","year":"2020","journal-title":"Biomolecules"},{"key":"pone.0247287.ref006","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1161\/01.CIR.94.11.2708","article-title":"Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms","volume":"94","author":"DM Milewicz","year":"1996","journal-title":"Circulation"},{"key":"pone.0247287.ref007","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/ng.934","article-title":"Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1","volume":"43","author":"SA LeMaire","year":"2011","journal-title":"Nat Genet"},{"key":"pone.0247287.ref008","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1038\/ng.2007.6","article-title":"Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections","volume":"39","author":"D-C Guo","year":"2007","journal-title":"Nat Genet"},{"key":"pone.0247287.ref009","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s41588-018-0265-y","article-title":"ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm","volume":"51","author":"RA Gould","year":"2019","journal-title":"Nat Genet"},{"key":"pone.0247287.ref010","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.jvs.2017.12.023","article-title":"Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center","volume":"68","author":"KL Hicks","year":"2018","journal-title":"J Vasc Surg"},{"key":"pone.0247287.ref011","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"C Bycroft","year":"2018","journal-title":"Nature"},{"key":"pone.0247287.ref012","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: rising to the challenge of larger and richer datasets","volume":"4","author":"CC Chang","year":"2015","journal-title":"Gigascience"},{"key":"pone.0247287.ref013","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.atherosclerosis.2007.05.018","article-title":"ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques","volume":"196","author":"D W\u00e5gs\u00e4ter","year":"2008","journal-title":"Atherosclerosis"},{"key":"pone.0247287.ref014","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.1021\/pr100250s","article-title":"Profile of macrophages in human abdominal aortic aneurysms: a transcriptomic, proteomic, and antibody protein array study","volume":"9","author":"N Lamblin","year":"2010","journal-title":"J Proteome Res"},{"key":"pone.0247287.ref015","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1161\/CIRCULATIONAHA.120.047544","article-title":"Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program","volume":"142","author":"D Klarin","year":"2020","journal-title":"Circulation"},{"key":"pone.0247287.ref016","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ijcard.2020.03.072","article-title":"Experimental abdominal aortic aneurysm growth is inhibited by blocking the JAK2\/STAT3 pathway","volume":"312","author":"J Xiao","year":"2020","journal-title":"Int J Cardiol"},{"key":"pone.0247287.ref017","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41419-020-2326-2","article-title":"A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy","volume":"11","author":"Q-Y Wu","year":"2020","journal-title":"Cell Death Dis"},{"key":"pone.0247287.ref018","first-page":"1428","article-title":"The role of Hath6, a newly identified shear-stress-responsive transcription factor, in endothelial cell differentiation and function","volume":"127","author":"F Fang","year":"2014","journal-title":"J Cell Sci"},{"key":"pone.0247287.ref019","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1373\/clinchem.2011.172759","article-title":"9p21 and the genetic revolution for coronary artery disease","volume":"58","author":"R Roberts","year":"2012","journal-title":"Clin Chem"},{"key":"pone.0247287.ref020","doi-asserted-by":"crossref","first-page":"E10","DOI":"10.3171\/2019.4.FOCUS19204","article-title":"Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era","volume":"47","author":"N Samuel","year":"2019","journal-title":"Neurosurg Focus"},{"key":"pone.0247287.ref021","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s10897-016-0029-8","article-title":"A Review of the Genetics of Intracranial Berry Aneurysms and Implications for Genetic Counseling","volume":"26","author":"E Hitchcock","year":"2017","journal-title":"J Genet Couns"},{"key":"pone.0247287.ref022","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.1142842","article-title":"A common variant on chromosome 9p21 affects the risk of myocardial infarction","volume":"316","author":"A Helgadottir","year":"2007","journal-title":"Science"},{"key":"pone.0247287.ref023","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/ng.72","article-title":"The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm","volume":"40","author":"A Helgadottir","year":"2008","journal-title":"Nat Genet"},{"key":"pone.0247287.ref024","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1093\/hmg\/ddt141","article-title":"A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm","volume":"22","author":"GT Jones","year":"2013","journal-title":"Hum Mol Genet"},{"key":"pone.0247287.ref025","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1055\/s-0038-1657771","article-title":"Abdominal Aortic Aneurysm: Evolving Controversies and Uncertainties","volume":"27","author":"D Carino","year":"2018","journal-title":"Int J Angiol"},{"key":"pone.0247287.ref026","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1093\/eurheartj\/ehs373","article-title":"Mutations in the area composita protein \u03b1T-catenin are associated with arrhythmogenic right ventricular cardiomyopathy","volume":"34","author":"J van Hengel","year":"2013","journal-title":"Eur Heart J"},{"key":"pone.0247287.ref027","doi-asserted-by":"crossref","first-page":"70080","DOI":"10.18632\/oncotarget.12148","article-title":"FRMD6 inhibits human glioblastoma growth and progression by negatively regulating activity of receptor tyrosine kinases","volume":"7","author":"Y Xu","year":"2016","journal-title":"Oncotarget"},{"key":"pone.0247287.ref028","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00701-019-04185-9","article-title":"Serum myelin basic protein as a marker of brain injury in aneurysmal subarachnoid haemorrhage","volume":"162","author":"N W\u0105sik","year":"2020","journal-title":"Acta Neurochir (Wien)"},{"key":"pone.0247287.ref029","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.gene.2016.07.033","article-title":"FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders","volume":"591","author":"LY Sakai","year":"2016","journal-title":"Gene"},{"key":"pone.0247287.ref030","article-title":"Deep learning enables genetic analysis of the human thoracic aorta","author":"JP Pirruccello","year":"2020","journal-title":"bioRxiv"},{"key":"pone.0247287.ref031","unstructured":"Anon. FinnGen Documentation of R4 release. https:\/\/finngen.gitbook.io\/documentation\/. Accessed December 16, 2020."},{"key":"pone.0247287.ref032","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1161\/CIRCRESAHA.116.308765","article-title":"Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci","volume":"120","author":"GT Jones","year":"2017","journal-title":"Circ Res"},{"key":"pone.0247287.ref033","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1161\/CIRCRESAHA.118.312436","article-title":"Genetics of Thoracic and Abdominal Aortic Diseases","volume":"124","author":"A Pinard","year":"2019","journal-title":"Circulation Research"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247287","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T13:29:06Z","timestamp":1630502946000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247287"}},"subtitle":[],"editor":[{"given":"Danillo G","family":"Augusto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,9,1]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0247287","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.02.05.429911","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,1]]}}}