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

Research output: Contribution to journalArticle

106 Scopus citations

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

ASJC Scopus subject areas

  • Genetics

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