Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program

Abstract

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.

Fig. 1. Overall study design.

In the current study, we first performed a TAAD discovery GWAS in the MVP, with replication from six external datasets. Secondary analyses included a PheWAS of lead TAAD risk variants, MR analyses with known epidemiologic risk factors for disease, a series of analyses to identify causal genes, variants and cell types for TAAD leveraging colocalization techniques and scRNA-seq or snRNA-seq data, and the generation and testing of a TAAD PRS. This figure was created with the assistance of BioRender. Abbreviations: LDL-C, LDL cholesterol; HDL-C, HDL cholesterol; TG, triglycerides; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Fig. 2. Anatomic distribution of TAAD risk variants in the thoracic aorta.

a, Descending aortic diameter Z scores (x axis) and ascending aortic diameter Z scores (y axis) for the 21 TAAD lead risk variants in our study queried in previously published summary statistics from the UK Biobank (n = 39,688 individuals). b, Difference in effect estimates (β_ascending – β_descending) and associated 95% CIs (error bars) for the 21 TAAD lead risk variants in our study queried in previously published summary statistics from the UK Biobank (n = 39,688 individuals). AscAo, ascending aorta; DescAo, descending aorta. Variants were declared to be significantly associated with the respective diameter if the linear mixed-model two-sided P value of association was <0.0012. Variants significantly associated with the diameter of the ascending aorta (green), the descending aorta (blue) or both ascending and descending aortic diameters (orange) are displayed.

Fig. 3. MR analyses of epidemiologic risk factors for TAAD.

Logistic regression (inverse-variance-weighted; IVW) association results for multiple epidemiologic risk factor exposures with the TAAD outcome in two-sample MR analyses. The lifetime smoking TAAD OR reflects a per-genetic increase in smoking ~20 cigarettes a day for 15 years and stopping 17 years ago. The OR for height reflects a 1-s.d. genetic increase in standing height (~7.6 cm). The SBP, DBP, MAP and PP ORs correspond to the change in TAAD risk per 10-mmHg increase in the blood pressure trait. The lipid ORs reflect the change in TAAD risk per s.d. genetic increase in lipid fraction. Two-sided P values are displayed, and we set a two-sided P < 0.0055 (0.05 ÷ 9 traits) for statistical significance. Error bars represent 95% CIs of the displayed ORs.

Fig. 4. Causal TAAD cell types.

Dot plots for each of the nine candidate causal genes likely affecting TAAD risk based on changes in gene expression in scRNA-seq data from aneurysmal and unaffected ascending aortas (a) and snRNA-seq data from unaffected ascending and descending thoracic aortas (b). c, t-distributed stochastic neighbor embedding (t-SNE) plot of cell type clusters for scRNA-seq data from aneurysmal and unaffected ascending thoracic aortas. Violin plots (d) and relative expression (e) of each of the nine candidate causal genes likely affecting TAAD risk based on changes in gene expression for each cell type. *Two-sided P value < 0.005 after Bonferroni correction for the maximum number of tests in each cluster (nine) when performing the Wilcoxon rank-sum test for differential expression in aneurysmal ascending thoracic aortic tissue versus unaffected tissue. f, Prioritized cell type(s) for each of the nine candidate causal genes above depicted along a representative thoracic aortic cross-section. This figure was created with the assistance of BioRender. Abbreviations: AA, ascending aorta; TA, thoracic aorta; ATA, ascending thoracic aneurysm; scRNA-seq, scRNA-seq data; snRNA-seq, snRNA-seq data; SMC, smooth muscle cell; MonoMaphDC, monocyte–macrophage–dendritic cell; NK, natural killer cell; EC, endothelial cell; ?, unclear cell type as referenced; MSC, mesothelial cell or mesenchymal–stromal cell.

Fig. 5. TAAD polygenic risk.

a, Logistic regression ORs and two-sided P values for the association of the top 5% of the TAAD PRS with prevalent TAAD in the Mass General Brigham and CHIP–MGI biobanks. Results were combined in an inverse-variance-weighted fixed-effect meta-analysis. b, Hazard ratios and two-sided P values for the association of the top 5% of the TAAD PRS with incident TAAD and TAAD-related death in the UK Biobank. Error bars represent 95% CIs of the displayed ORs. Abbreviations: MGBB, Mass General Brigham Biobank; UKBB, UK Biobank.