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Original Contribution

Familial Intracranial Aneurysms

Is Anatomic Vulnerability Heritable?

Jason Mackey, Robert D. Brown, Charles J. Moomaw, Richard Hornung, Laura Sauerbeck, Daniel Woo, Tatiana Foroud, Dheeraj Gandhi, Dawn Kleindorfer, Matthew L. Flaherty, Irene Meissner, Craig Anderson, Guy Rouleau, E. Sander Connolly, Ranjan Deka, Daniel L. Koller, Todd Abruzzo, John Huston, Joseph P. Broderick, For the FIA Investigators
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https://doi.org/10.1161/STROKEAHA.112.667261
Stroke. 2013;44:38-42
Originally published December 24, 2012
Jason Mackey
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Robert D. Brown
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Charles J. Moomaw
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Richard Hornung
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Laura Sauerbeck
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Daniel Woo
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Tatiana Foroud
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Dheeraj Gandhi
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Dawn Kleindorfer
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Matthew L. Flaherty
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Irene Meissner
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Craig Anderson
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Guy Rouleau
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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E. Sander Connolly
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Ranjan Deka
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Daniel L. Koller
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Todd Abruzzo
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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John Huston
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Joseph P. Broderick
From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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From the Department of Neurology (J.M.) and Department of Medical and Molecular Genetics (T.F., D.L.K.), Indiana University, Indianapolis, IN; Department of Neurology (R.D.B.) and Department of Radiology (J.H.), Mayo Clinic, Rochester, MN; Department of Neurology (C.J.M., L.S., D.W., D.K., M.L.F., J.P.B.), Department of Emergency Medicine (R.H.), Department of Environmental Health (R.D.), and Department of Radiology (T.A.), University of Cincinnati, Cincinnati, OH; Department of Radiology, University of Maryland, Baltimore, MD (D.G.); The George Institute for International Health, University of Sydney, Sydney, Australia (C.A.); Notre Dame Hospital, University of Montreal, Montreal, Canada (G.R.); and Department of Neurosurgery, Columbia University, New York, NY (E.S.C.).
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Abstract

Background and Purpose—Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study.

Methods—We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family’s proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis.

Results—There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04–2.27]; P=0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22–3.22]; P=0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05–8.24], P=0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34–2.46]; P<0.001).

Conclusions—In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.

  • concordance
  • epidemiology
  • familial
  • genetics in stroke
  • heritability
  • intracranial aneurysm
  • Received June 11, 2012.
  • Revision received October 3, 2012.
  • Accepted October 17, 2012.
  • © 2012 American Heart Association, Inc.
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    Familial Intracranial Aneurysms
    Jason Mackey, Robert D. Brown, Charles J. Moomaw, Richard Hornung, Laura Sauerbeck, Daniel Woo, Tatiana Foroud, Dheeraj Gandhi, Dawn Kleindorfer, Matthew L. Flaherty, Irene Meissner, Craig Anderson, Guy Rouleau, E. Sander Connolly, Ranjan Deka, Daniel L. Koller, Todd Abruzzo, John Huston, Joseph P. Broderick and For the FIA Investigators
    Stroke. 2013;44:38-42, originally published December 24, 2012
    https://doi.org/10.1161/STROKEAHA.112.667261

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    Familial Intracranial Aneurysms
    Jason Mackey, Robert D. Brown, Charles J. Moomaw, Richard Hornung, Laura Sauerbeck, Daniel Woo, Tatiana Foroud, Dheeraj Gandhi, Dawn Kleindorfer, Matthew L. Flaherty, Irene Meissner, Craig Anderson, Guy Rouleau, E. Sander Connolly, Ranjan Deka, Daniel L. Koller, Todd Abruzzo, John Huston, Joseph P. Broderick and For the FIA Investigators
    Stroke. 2013;44:38-42, originally published December 24, 2012
    https://doi.org/10.1161/STROKEAHA.112.667261
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