Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities

Catherine M. Francis, Matthias E. Futschik, Jian Huang, Wenjia Bai, Muralidharan Sargurupremraj, Alexander Teumer, Monique M.B. Breteler, Enrico Petretto, Amanda S.R. Ho, Philippe Amouyel, Stefan T. Engelter, Robin Bülow, Uwe Völker, Henry Völzke, Marcus Dörr, Mohammed Aslam Imtiaz, N. Ahmad Aziz, Valerie Lohner, James S. Ware, Stephanie DebettePaul Elliott, Abbas Dehghan, Paul M. Matthews

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

Original languageEnglish (US)
Article number4505
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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