Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

Scott A. Lemaire, Merry Lynn N McDonald, Dong Chuan Guo, Ludivine Russell, Charles C. Miller, Ralph J. Johnson, Mir Reza Bekheirnia, Luis M. Franco, Mary Nguyen, Reed E. Pyeritz, Joseph E. Bavaria, Richard Devereux, Cheryl Maslen, Kathryn Holmes, Kim Eagle, Simon C. Body, Christine Seidman, J. G. Seidman, Eric M. Isselbacher, Molly BrayJoseph S. Coselli, Anthony L. Estrera, Hazim J. Safi, John W. Belmont, Suzanne M. Leal, Dianna M. Milewicz

    Research output: Contribution to journalArticle

    100 Citations (Scopus)

    Abstract

    Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P <1 × 10 -5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.

    Original languageEnglish (US)
    Pages (from-to)996-1002
    Number of pages7
    JournalNature Genetics
    Volume43
    Issue number10
    DOIs
    StatePublished - Oct 2011

    Fingerprint

    Thoracic Aortic Aneurysm
    Genome-Wide Association Study
    Dissection
    Single Nucleotide Polymorphism
    Marfan Syndrome
    Aortic Diseases
    Linkage Disequilibrium
    Genetic Predisposition to Disease
    Odds Ratio
    1,3,4,6-tetra-O-acetyl-2-azido-2-deoxyglucopyranose
    Genome
    Mutation
    Genes

    ASJC Scopus subject areas

    • Genetics

    Cite this

    Lemaire, S. A., McDonald, M. L. N., Guo, D. C., Russell, L., Miller, C. C., Johnson, R. J., ... Milewicz, D. M. (2011). Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nature Genetics, 43(10), 996-1002. https://doi.org/10.1038/ng.934

    Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. / Lemaire, Scott A.; McDonald, Merry Lynn N; Guo, Dong Chuan; Russell, Ludivine; Miller, Charles C.; Johnson, Ralph J.; Bekheirnia, Mir Reza; Franco, Luis M.; Nguyen, Mary; Pyeritz, Reed E.; Bavaria, Joseph E.; Devereux, Richard; Maslen, Cheryl; Holmes, Kathryn; Eagle, Kim; Body, Simon C.; Seidman, Christine; Seidman, J. G.; Isselbacher, Eric M.; Bray, Molly; Coselli, Joseph S.; Estrera, Anthony L.; Safi, Hazim J.; Belmont, John W.; Leal, Suzanne M.; Milewicz, Dianna M.

    In: Nature Genetics, Vol. 43, No. 10, 10.2011, p. 996-1002.

    Research output: Contribution to journalArticle

    Lemaire, SA, McDonald, MLN, Guo, DC, Russell, L, Miller, CC, Johnson, RJ, Bekheirnia, MR, Franco, LM, Nguyen, M, Pyeritz, RE, Bavaria, JE, Devereux, R, Maslen, C, Holmes, K, Eagle, K, Body, SC, Seidman, C, Seidman, JG, Isselbacher, EM, Bray, M, Coselli, JS, Estrera, AL, Safi, HJ, Belmont, JW, Leal, SM & Milewicz, DM 2011, 'Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1', Nature Genetics, vol. 43, no. 10, pp. 996-1002. https://doi.org/10.1038/ng.934
    Lemaire, Scott A. ; McDonald, Merry Lynn N ; Guo, Dong Chuan ; Russell, Ludivine ; Miller, Charles C. ; Johnson, Ralph J. ; Bekheirnia, Mir Reza ; Franco, Luis M. ; Nguyen, Mary ; Pyeritz, Reed E. ; Bavaria, Joseph E. ; Devereux, Richard ; Maslen, Cheryl ; Holmes, Kathryn ; Eagle, Kim ; Body, Simon C. ; Seidman, Christine ; Seidman, J. G. ; Isselbacher, Eric M. ; Bray, Molly ; Coselli, Joseph S. ; Estrera, Anthony L. ; Safi, Hazim J. ; Belmont, John W. ; Leal, Suzanne M. ; Milewicz, Dianna M. / Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. In: Nature Genetics. 2011 ; Vol. 43, No. 10. pp. 996-1002.
    @article{5c2c3e5269ff45fe9fbfae93b2c7316d,
    title = "Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1",
    abstract = "Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P <1 × 10 -5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.",
    author = "Lemaire, {Scott A.} and McDonald, {Merry Lynn N} and Guo, {Dong Chuan} and Ludivine Russell and Miller, {Charles C.} and Johnson, {Ralph J.} and Bekheirnia, {Mir Reza} and Franco, {Luis M.} and Mary Nguyen and Pyeritz, {Reed E.} and Bavaria, {Joseph E.} and Richard Devereux and Cheryl Maslen and Kathryn Holmes and Kim Eagle and Body, {Simon C.} and Christine Seidman and Seidman, {J. G.} and Isselbacher, {Eric M.} and Molly Bray and Coselli, {Joseph S.} and Estrera, {Anthony L.} and Safi, {Hazim J.} and Belmont, {John W.} and Leal, {Suzanne M.} and Milewicz, {Dianna M.}",
    year = "2011",
    month = "10",
    doi = "10.1038/ng.934",
    language = "English (US)",
    volume = "43",
    pages = "996--1002",
    journal = "Nature Genetics",
    issn = "1061-4036",
    publisher = "Nature Publishing Group",
    number = "10",

    }

    TY - JOUR

    T1 - Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

    AU - Lemaire, Scott A.

    AU - McDonald, Merry Lynn N

    AU - Guo, Dong Chuan

    AU - Russell, Ludivine

    AU - Miller, Charles C.

    AU - Johnson, Ralph J.

    AU - Bekheirnia, Mir Reza

    AU - Franco, Luis M.

    AU - Nguyen, Mary

    AU - Pyeritz, Reed E.

    AU - Bavaria, Joseph E.

    AU - Devereux, Richard

    AU - Maslen, Cheryl

    AU - Holmes, Kathryn

    AU - Eagle, Kim

    AU - Body, Simon C.

    AU - Seidman, Christine

    AU - Seidman, J. G.

    AU - Isselbacher, Eric M.

    AU - Bray, Molly

    AU - Coselli, Joseph S.

    AU - Estrera, Anthony L.

    AU - Safi, Hazim J.

    AU - Belmont, John W.

    AU - Leal, Suzanne M.

    AU - Milewicz, Dianna M.

    PY - 2011/10

    Y1 - 2011/10

    N2 - Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P <1 × 10 -5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.

    AB - Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P <1 × 10 -5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.

    UR - http://www.scopus.com/inward/record.url?scp=80053385386&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=80053385386&partnerID=8YFLogxK

    U2 - 10.1038/ng.934

    DO - 10.1038/ng.934

    M3 - Article

    C2 - 21909107

    AN - SCOPUS:80053385386

    VL - 43

    SP - 996

    EP - 1002

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

    IS - 10

    ER -