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

• Published in: Nature genetics Vol. 43; no. 10; pp. 996 - 1000
• Main Authors: Milewicz, Dianna M, 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 W, 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2011; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/727/2000; 631/443/592/1287; Agriculture; Aneurysms; Animal Genetics and Genomics; Aortic Aneurysm, Thoracic - genetics; Aortic Aneurysm, Thoracic - pathology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood and lymphatic vessels; Cancer Research; Cardiology. Vascular system; Case-Control Studies; Chromosomes, Human, Pair 15 - genetics; Disease susceptibility; Diseases of the aorta; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dissection; DNA - genetics; DNA - isolation & purification; Fibrillin-1; Fibrillins; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetic Loci; Genetic Predisposition to Disease; Genetic variance; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; Genotyping Techniques; Hospitals; Human Genetics; Humans; letter; Linkage Disequilibrium; Marfan syndrome; Marfan Syndrome - genetics; Medical sciences; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Mutation; Polymorphism, Single Nucleotide; Risk factors; Sequence Analysis, DNA; Single nucleotide polymorphisms; Thoracic surgery; United States; Arterial disease; Vascular disease; Sensitivity; Association; Susceptibility locus; Cardiovascular disease; Aortic dissection; Identification; Aortic aneurysm; Aortic disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.934

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.