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.

Figure 1

A Manhattan plot of stage 1 genome-wide association results from comparison of STAAD cases to NINDS controls. For each tested marker, the significance is displayed on the y-axis as the −log₁₀ of the P value. The −log₁₀ results are ordered along the x-axis by chromosome, with each colored bar representing a different chromosome.

Figure 2

FBN1 regional association plots. (a–c) Association plots are shown for STAAD (a), STAAD with BAV (b) and aortic dissection (c). The top-ranked stage 1 SNP for each phenotype is marked by a blue diamond. Red, pink and yellow shading denotes r² (see key), corresponding to the linkage disequilibrium between the top-ranked SNP and other SNPs in the region. The recombination rate according to HapMap CEU is plotted as a light blue line, with amplitude scaled to the right-hand y-axis. Circles denote the five SNPs genotyped in the FBN1 region that were associated with TAAD in stage 1 with GWS. Dotted lines denote −log₁₀ P = 0. Green triangles denote the fixed-effects meta-analysis results for the combined stages. When the result of the Cochran Q test of homogeneity was <0.1, random-effects meta-analysis results are shown; otherwise fixed-effects meta-analysis was performed.