title: Familial intracranial aneurysms: is anatomic vulnerability heritable?
abstract: OBJECTIVE
  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.
authors.affiliation: IU Health Neuroscience Center, 355 W 16th St, Suite 3200, Indianapolis, IN 46202, USA. jsmackey@iupui.edu
authors.forename: Jason
authors.initials: J
authors.lastname: Mackey
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brown
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Moomaw
authors.forename: Richard
authors.initials: R
authors.lastname: Hornung
authors.forename: Laura
authors.initials: L
authors.lastname: Sauerbeck
authors.forename: Daniel
authors.initials: D
authors.lastname: Woo
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Gandhi
authors.forename: Dawn
authors.initials: D
authors.lastname: Kleindorfer
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Flaherty
authors.forename: Irene
authors.initials: I
authors.lastname: Meissner
authors.forename: Craig
authors.initials: C
authors.lastname: Anderson
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
authors.forename: Ranjan
authors.initials: R
authors.lastname: Deka
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Koller
authors.forename: Todd
authors.initials: T
authors.lastname: Abruzzo
authors.forename: John
authors.initials: J
authors.lastname: Huston
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Broderick
mesh_terms: D000328:Adult; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D019655:Quantitative Trait, Heritable