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 W. Holmes; Kim Eagle; Simon C. Body; Christine Seidman; J. G. Seidman; Eric M. Isselbacher; Molly Bray; Joseph S. Coselli; Anthony L. Estrera; Hazim J. Safi; John W. Belmont; Suzanne M. Leal; Dianna M. Milewicz

doi:10.1038/ng.934

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 W. 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	996-1002
Number of pages	7
Journal	Nature Genetics
Volume	43
Issue number	10
DOIs	https://doi.org/10.1038/ng.934
State	Published - Oct 2011

ASJC Scopus subject areas

Genetics

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Lemaire, S. A., McDonald, M. L. N., Guo, D. C., Russell, L., Miller, C. C., Johnson, R. J., Bekheirnia, M. R., Franco, L. M., Nguyen, M., Pyeritz, R. E., Bavaria, J. E., Devereux, R., Maslen, C., Holmes, K. W., Eagle, K., Body, S. C., Seidman, C., Seidman, J. G., Isselbacher, E. M., ... 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

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, KW, 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

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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 Holmes, {Kathryn W.} 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.}",

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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 W.

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.

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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.

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

Abstract

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