Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.

<h4>Background</h4>Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component.<h4>Methods and results</h4>In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA...

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Autores principales:	Tamara Ashvetiya, Sherry X Fan, Yi-Ju Chen, Charles H Williams, Jeffery R O'Connell, James A Perry, Charles C Hong
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a0505206eb8a4cd58caac22450681d78
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spelling	oai:doaj.org-article:a0505206eb8a4cd58caac22450681d782021-12-02T20:06:21ZIdentification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.1932-620310.1371/journal.pone.0247287https://doaj.org/article/a0505206eb8a4cd58caac22450681d782021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0247287https://doaj.org/toc/1932-6203<h4>Background</h4>Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component.<h4>Methods and results</h4>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) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP 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 FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA.<h4>Conclusions</h4>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 JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.Tamara AshvetiyaSherry X FanYi-Ju ChenCharles H WilliamsJeffery R O'ConnellJames A PerryCharles C HongPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0247287 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tamara Ashvetiya Sherry X Fan Yi-Ju Chen Charles H Williams Jeffery R O'Connell James A Perry Charles C Hong Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
description	<h4>Background</h4>Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component.<h4>Methods and results</h4>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) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP 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 FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA.<h4>Conclusions</h4>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 JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.
format	article
author	Tamara Ashvetiya Sherry X Fan Yi-Ju Chen Charles H Williams Jeffery R O'Connell James A Perry Charles C Hong
author_facet	Tamara Ashvetiya Sherry X Fan Yi-Ju Chen Charles H Williams Jeffery R O'Connell James A Perry Charles C Hong
author_sort	Tamara Ashvetiya
title	Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
title_short	Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
title_full	Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
title_fullStr	Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
title_full_unstemmed	Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.
title_sort	identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the uk biobank cohort.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a0505206eb8a4cd58caac22450681d78
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Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.

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