Rare copy number variants disrupt genes regulating vascular smooth muscle cell adhesion and contractility in sporadic thoracic aortic aneurysms and dissections

Am J Hum Genet. 2010 Dec 10;87(6):743-56. doi: 10.1016/j.ajhg.2010.09.015. Epub 2010 Nov 18.


Thoracic aortic aneurysms and dissections (TAAD) cause significant morbidity and mortality, but the genetic origins of TAAD remain largely unknown. In a genome-wide analysis of 418 sporadic TAAD cases, we identified 47 copy number variant (CNV) regions that were enriched in or unique to TAAD patients compared to population controls. Gene ontology, expression profiling, and network analysis showed that genes within TAAD CNVs regulate smooth muscle cell adhesion or contractility and interact with the smooth muscle-specific isoforms of α-actin and β-myosin, which are known to cause familial TAAD when altered. Enrichment of these gene functions in rare CNVs was replicated in independent cohorts with sporadic TAAD (STAAD, n = 387) and inherited TAAD (FTAAD, n = 88). The overall prevalence of rare CNVs (23%) was significantly increased in FTAAD compared with STAAD patients (Fisher's exact test, p = 0.03). Our findings suggest that rare CNVs disrupting smooth muscle adhesion or contraction contribute to both sporadic and familial disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / pathology
  • Aortic Aneurysm, Thoracic / physiopathology
  • Cell Adhesion / genetics*
  • Female
  • Gene Dosage*
  • Humans
  • Male
  • Middle Aged
  • Muscle Contraction / genetics
  • Muscle, Smooth, Vascular / pathology*
  • Muscle, Smooth, Vascular / physiopathology