4.8 Article

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

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32219-x

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资金

  1. NHLI
  2. BHF Imperial Centre of Research Excellence [RE/18/4/34215]
  3. BHF Clinical Research Fellowship [FS/15/81/31817]
  4. Edmond J Safra Foundation
  5. National Institute for Health Research (NIHR)
  6. UK Dementia Research Institute
  7. NIHR Biomedical Research Centre at Imperial College London
  8. Medical Research Council (UK)
  9. British Heart Foundation [RE/18/4/34215]
  10. NIHR Imperial College Biomedical Research Centre
  11. Sir Jules Thorn Charitable Trust [21/JTA]
  12. MRC [MR/L01341X/1, MR/S019669/1]
  13. NIHR
  14. NIHR Imperial Biomedical Research Centre
  15. Imperial College British Heart Foundation Centre for Research Excellence [RE/18/4/34215]
  16. UK Dementia Research Institute at Imperial College London [MC_PC_17114]
  17. Health Data Research UK for London
  18. French National Research Agency (ANR) [ANR-18-RHUS-002]
  19. ERC
  20. EU H2020 [640643, 667375, 754517]
  21. Inserm
  22. Lille 2 University
  23. Institut Pasteur de Lille
  24. Lille University Hospital
  25. ERDF (FEDER funds)
  26. Region Nord-Pas de-Calais [09120030]
  27. Centre National de Genotypage
  28. Emil Aaltonen Foundation
  29. Paavo Ilmari Ahvenainen Foundation
  30. Helsinki University Central Hospital Research Fund
  31. Helsinki University Medical Foundation
  32. Paivikki and Sakari Sohlberg Foundation
  33. Aarne Koskelo Foundation
  34. Maire Taponen Foundation
  35. Aarne and Aili Turunen Foundation
  36. Lilly Foundation
  37. Alfred Kordelin Foundation
  38. Finnish Medical Foundation
  39. Orion Farmos Research Foundation
  40. Maud Kuistila Foundation
  41. Finnish Brain Foundation
  42. Biomedicum Helsinki Foundation
  43. Projet Hospitalier de Recherche Clinique Regional
  44. Fondation de France
  45. Genopole de Lille
  46. Adrinord
  47. Basel Stroke-Funds
  48. Kathe-Zingg-Schwichtenberg Fonds of the Swiss Academy of Medical Sciences
  49. Swiss Heart Foundation
  50. Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A]
  51. Ministry of Cultural Affairs
  52. Social Ministry of the Federal State of Mecklenburg West Pomerania
  53. Siemens Healthineers, Erlangen, Germany
  54. Federal State of Mecklenburg-West Pomerania
  55. Lily Safra

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The study identifies genetic variants associated with aortic distensibility, highlighting the causal relationships between aortic distensibility and aortic aneurysms as well as brain small vessel disease. The findings provide new insights into the mechanisms related to cardiovascular development, extracellular matrix production, and smooth muscle cell contraction.
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease. 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-beta, 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.

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