Genomic insights in ascending aortic size and distensibility
Jan Walter Benjamins,
Ming Wai Yeung,
Yordi J. van de Vegte,
M. Abdullah Said,
Thijs van der Linden,
Daan Ties,
Luis E. Juarez-Orozco,
Niek Verweij,
Pim van der Harst
Affiliations
Jan Walter Benjamins
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands; Corresponding author.
Ming Wai Yeung
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands; Department of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherland
Yordi J. van de Vegte
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
M. Abdullah Said
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
Thijs van der Linden
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
Daan Ties
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
Luis E. Juarez-Orozco
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands; Department of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherland
Niek Verweij
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands
Pim van der Harst
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands; Department of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherland
Summary: Background: Alterations in the anatomic and biomechanical properties of the ascending aorta (AAo) can give rise to various vascular pathologies. The aim of the current study is to gain additional insights in the biology of the AAo size and function. Methods: We developed an AI based analysis pipeline for the segmentation of the AAo, and the extraction of AAO parameters. We then performed genome-wide association studies of AAo maximum area, AAo minimum area and AAo distensibility in up to 37,910 individuals from the UK Biobank. Variants that were significantly associated with AAo phenotypes were used as instrumental variables in Mendelian randomization analyses to investigate potential causal relationships with coronary artery disease, myocardial infarction, stroke and aneurysms. Findings: Genome-wide association studies revealed a total of 107 SNPs in 78 loci. We annotated 101 candidate genes involved in various biological processes, including connective tissue development (THSD4 and COL6A3). Mendelian randomization analyses showed a causal association with aneurysm development, but not with other vascular diseases. Interpretation: We identified 78 loci that provide insights into mechanisms underlying AAo size and function in the general population and provide genetic evidence for their role in aortic aneurysm development.
