Aortic caliber is a quantitative trait on a continuous spectrum from stenosis to aneurysm.

Aortic size in healthy people is primarily influenced by common genetic variants.

Mendelian disease variants dramatically shift this distribution larger or smaller.

Variation in genes/pathways influence aortic size in a context-dependent manner.

Future inclusion of modifier loci will improve clinical care and risk prediction.

The size of the aorta varies in the healthy population and is influenced by a series of mostly common and lower-impact genomic variants. Rare, high-impact variants driving Mendelian diseases of stenosis and aneurysm extend the limits of aortic size out of the typical range. Pathology at both ends of the spectrum is governed by overlapping pathways and processes, such as those affecting structure, integrity, and function of the aorta. As such, aortopathies across the full spectrum from stenosis to aneurysm are likely modified by a similar constellation of common and rarer genetic variants in a directional, weighted, and context-dependent manner. Here, we discuss the role of modifiers in aortic disease by presenting an example of two opposing rare diseases and highlight the need to consider the influence of background genome variation when considering disease outcomes.

aorta size

elastin

aortic aneurysm

stenosis

modifier

polygenic risk

Published by Elsevier Ltd.