AORTA Gene: Polygenic prediction improves detection of thoracic aortic aneurysm

Abstract

Background: Thoracic aortic disease is an important cause of morbidity and mortality in the US, and aortic diameter is a heritable contributor to risk. Could a polygenic prediction of ascending aortic diameter improve detection of aortic aneurysm?

Methods: Deep learning was used to measure ascending thoracic aortic diameter in 49,939 UK Biobank participants. A genome-wide association study (GWAS) was conducted in 39,524 participants and leveraged to build a 1.1 million-variant polygenic score with PRScs-auto. Aortic diameter prediction models were built with the polygenic score ("AORTA Gene") and without it. The models were tested in a held-out set of 4,962 UK Biobank participants and externally validated in 5,469 participants from Mass General Brigham Biobank (MGB), 1,298 from the Framingham Heart Study (FHS), and 610 participants from All of Us.

Results: In each test set, the AORTA Gene model explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.9% (95% CI 37.8-42.0%) vs 29.2% (95% CI 27.1-31.4%) in UK Biobank, 36.5% (95% CI 34.4-38.5%) vs 32.5% (95% CI 30.4-34.5%) in MGB, 41.8% (95% CI 37.7-45.9%) vs 33.0% (95% CI 28.9-37.2%) in FHS, and 34.9% (95% CI 28.8-41.0%) vs 28.9% (95% CI 22.9-35.0%) in All of Us. AORTA Gene had a greater AUROC for identifying diameter ≥4cm in each test set: 0.834 vs 0.765 (P=7.3E-10) in UK Biobank, 0.808 vs 0.767 in MGB (P=4.5E-12), 0.856 vs 0.818 in FHS (P=8.5E-05), and 0.827 vs 0.791 (P=7.8E-03) in All of Us.

Conclusions: Genetic information improved estimation of thoracic aortic diameter when added to clinical risk factors. Larger and more diverse cohorts will be needed to develop more powerful and equitable scores.

Keywords: All of Us; Ascending aorta; Framingham Heart Study; Mass General Brigham; UK Biobank; polygenic score.

Figure 1:. Study cohorts

The sample diagram depicts participant subsets. UK Biobank participants with MRI data were split by random ID into a GWAS group (blue, N=39,524) and a residual group. Individuals in the residual group related within 3 degrees of kinship were removed (N=557), and the residual group was then split into a training group (purple, N=4,896) and an internal validation group (yellow, N=4,962). As depicted in the legend, the GWAS and PRS development was conducted in the GWAS group (blue, N=39,524). Clinical model development was conducted in the GWAS and training groups (blue and purple, N=44,420). The PRS was incorporated into the clinical score using a linear model to produce the AORTA Gene model in the training group (purple, N=4,896). All models were validated in the internal validation set (yellow, N=4,962) and the external validation sets (orange): MGB, FHS, and All of Us. MGB: Mass General Brigham Biobank. FHS: Framingham Heart Study. MRI: magnetic resonance imaging. GWAS: genome-wide association study.

Figure 2:. Score calibration curves in the UK Biobank validation set

Counterclockwise from top left: AORTA Gene, followed by the clinical AORTA Score, the age and sex model, and the age/sex/genetics model. The x axis represents the predicted ascending aortic diameter; the y axis represents the measured ascending aortic diameter; both are truncated at the same points so that the x and y axes have the same span. Each point represents one of the 4,962 UK Biobank internal validation set participants; orange points represent women while navy points represent men. The blue line shows the smoothed average value, and only extends along the x axis to the limits of the observed data. The black line shows the line of ideal calibration, where a 1 cm greater score would be met by a 1 cm greater aortic diameter. For all plotted scores, the slopes were statistically indistinguishable from one and the intercepts were statistically indistinguishable from zero as detailed in the Results.

Figure 3:. Variance in aortic diameter explained by the models

For each cohort, the variance in ascending aortic diameter explained by the model derived from age and sex (navy blue), the clinical model (AORTA Score, slate gray), and the clinical model incorporating the polygenic score (AORTA Gene, orange) is depicted for the internal validation set and the three external validation sets. MGB: Mass General Brigham Biobank. FHS: Framingham Heart Study.

Figure 4:. Receiver operator characteristic curves

Receiver operator characteristic (ROC) curves for the AORTA Gene model (red) and the clinical AORTA Score model (blue) in the validation cohorts. The dashed diagonal line represents the no-information baseline. Counterclockwise from top left: UK Biobank internal validation, MGB, FHS, and All of Us. The AUROC for detecting aortic diameter ≥4cm for the AORTA Gene model in these cohorts was, respectively, 0.834, 0.808, 0.856, and 0.827. The respective AUROC for the clinical AORTA Score was 0.765, 0.767, 0.818, and 0.791. MGB: Mass General Brigham Biobank. FHS: Framingham Heart Study.