Abstract

Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6–1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10−5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (P50-HL083794 and R01-HL62594 to D.M.M.; UL1RR024148 and UL1RR025758 (CTSA); K08-HL080085 to S.A.L.), as well as the Doris Duke Charitable Trust, the Vivian L. Smith Foundation, the TexGen Foundation and the Thoracic Surgery Foundation for Research and Education.

GenTAC participating centers and their investigators are as follows: Johns Hopkins University School of Medicine, K.W.H., H.C. Dietz, W. Ravekes, K. Lurman; University of Texas Health Science Center at Houston, D.M.M., A. Carlson; Baylor College of Medicine, S.A.L., J.L. Jefferies, I.V. Volguina; Oregon Health & Science University, C.M., H.K. Song, V. Menashe, M. Silberbach, J.D. Kushner; Perelman School of Medicine at the University of Pennsylvania, R.E.P., J.E.B., M. Morales; Weill Cornell Medical College, C.T. Basson, R.D., J.W. Weinsaft, D. McDermott; University of Michigan Medical School, K.E.; US National Heart, Lung, and Blood Institute, H.E. Tolunay, P. Desvigne-Nickens, M.P. Stylianou, M. Mitchell; RTI International, B.L. Kroner, D. Brambilla, T. Hendershot, D. Ringer, M. Cunningham, M. Kindem. The GenTAC registry is supported by US Federal Government Contract N01-HV-68199 from the National Heart, Lung, and Blood Institute and by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

We thank the GenTAC investigators, collaborators and coordinators; NINDS and WTCCC for giving us the use of their control data; S.N. Palmer, N. Stancel and R. Bartow for editorial assistance; Y. Khalil for subject recruitment; Z. Ren for technical support; A. Kicza for her dedicated work contacting and talking to subjects; and all of the subjects who participated in this research. We thank the surgeons of Brigham and Women's Hospital: S.F. Aranki, R.M. Bolman III, F.Y. Chen, L.H. Cohn, G.S. Couper, M. Davidson, R.J. Rizzo and P. Shekar. We also thank the surgeons of Massachusetts General Hospital: A. Agnihotri, C. Akins, A.D. Hilgenberg, T.E. MacGillivray, J.C. Madsen, B.R. Rosengard, D.F. Torchiana, G.J. Vlahakes and J.D. Walker.

Author information

Author notes

    • Scott A LeMaire
    • , Merry-Lynn N McDonald
    •  & Dong-chuan Guo

    These authors contributed equally to this work.

Affiliations

  1. Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.

    • Scott A LeMaire
    • , Ludivine Russell
    • , Mary Nguyen
    •  & Joseph S Coselli
  2. Cardiovascular Surgery, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas, USA.

    • Scott A LeMaire
    • , Ludivine Russell
    • , Mary Nguyen
    •  & Joseph S Coselli
  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Merry-Lynn N McDonald
    • , Mir Reza Bekheirnia
    • , Luis M Franco
    • , John W Belmont
    •  & Suzanne M Leal
  4. Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Dong-chuan Guo
    • , Ralph J Johnson
    •  & Dianna M Milewicz
  5. Department of Cardiothoracic and Vascular Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Charles C Miller III
    • , Anthony L Estrera
    •  & Hazim J Safi
  6. Division of Medical Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Reed E Pyeritz
  7. Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Joseph E Bavaria
  8. Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

    • Richard Devereux
  9. Division of Cardiovascular Medicine, Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA.

    • Cheryl Maslen
  10. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Kathryn W Holmes
  11. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • Kim Eagle
  12. Department of Anesthesiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Simon C Body
  13. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Christine Seidman
    •  & J G Seidman
  14. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Eric M Isselbacher
  15. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

    • Molly Bray
  16. Medicine Services, Texas Heart Institute, St. Luke's Episcopal Hospital, Houston, Texas, USA.

    • Dianna M Milewicz

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Contributions

S.A.L., J.W.B. and D.M.M. were the principal investigators who conducted the study. S.A.L. and D.M.M. coordinated and oversaw the study. L.R., R.J.J., C.C.M., D.M.M., S.A.L., J.S.C., H.J.S. and A.L.E. participated in study enrollment for stages 1 and 2, helped gather related detailed clinical information and biological samples, and helped carry out the clinical analysis. R.E.P., J.E.B., R.D., C.M., K.W.H., K.E., S.C.B., C.S., J.G.S. and E.M.I. participated in study enrollment for stages 2 and 3 and helped gather related detailed clinical information and biological samples. D.G. and M.N. participated in the preparation of biological samples. M.B., J.W.B., M.R.B. and L.M.F. carried out the genotyping. M.-L.N.M. and S.M.L. were responsible for bioinformatics and all statistical analyses. S.A.L., M.-L.N.M., D.G., S.M.L. and D.M.M. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dianna M Milewicz.

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DOI

https://doi.org/10.1038/ng.934

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