The Familial Intracranial Aneurysm Linkage Study (FIA)

Our long-term objective is to identify susceptibility genes that are related to the formation of intracranial aneurysms (IA). Rupture of IAs occurs in 16,000 to 17,000 persons in the U.S. annually and nearly half of affected persons are dead within the first 30 days. An additional 6,000 to 7,000 persons with unruptured IAs are identified each year. Accumulated evidence indicates that a genetic component plays an important role in the development of IAs, but specific loci affecting the risk of IA have not been identified. The primary hypothesis of this study is that there are specific human chromosomal regions that are associated with an increased risk of IAs. Specific Aims of are:

1. Recruitment of 400 (475) families with multiple individuals who have an IA through 23 (25) referral centers throughout North America, Australia, and New Zealand that represent 35 (40) recruitment sites.
2. Ascertainment of interviews and blood samples from all affected family members as well as their first-degree relatives. White blood cells from living persons with an IA will be cryopreserved at Coriell Institute for Medical Research for future immortalization of cells lines as indicated.
3. Identification of unruptured IAs by obtaining MRAs in selected asymptomatic siblings (of affected individuals).
4. Completion of a 10 cM genome series in persons with IAs as well as the spouses and children of persons with an IA who are deceased. We will perform finer mapping of chromosomal regions with suggestive evidence of linkage in the genome screen.
5. Performance of a nonparametric (allele sharing) linkage analysis, including relevant environmental factors such as smoking, to identify chromosomal regions linked to IA. Reconstruction of the genotypes of deceased affected family members will be performed.

Identification of individuals who are genetically at high risk for the development of IAs would enable targeted and effective screening/prevention/treatment strategies to reduce the substantial mortality and morbidity associated with this devastating type of stroke. Only a multidisciplinary, collaborative effort to identify, accrue, and genotype FIA families will be successful in identifying sufficient high-risk families to characterize the genetic underpinnings of IA.

• Study Weblinks:
  • Familial Intracranial Aneurysm
• Study Design:
  • Family/Twin/Trios
• Study Type:
  • Family Linkage
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 2507
• Subject Sample Telemetry Report (SSTR)

• PubMed

Inclusion Criteria for Phenotype of IA - Definition of Affected Family Member

1. Ruptured or unruptured IA as demonstrated by intra-arterial cerebral angiography, surgery, or autopsy.
2. Patients with a severe non-traumatic SAH, who do not undergo cerebral angiography to document their aneurysm because of early mortality or vegetative condition, will be designated as SAH due to presumed IA rupture. Massive non-traumatic SAH that results in early death is almost always due to rupture of an IA. These persons will be included as an affected case if the following conditions are met: a) non-traumatic abrupt onset of severe headache or altered level of consciousness that is associated with blood in the subarachnoid space on CT or at autopsy, b) widespread SAH by CT or autopsy, not limited to the interpeduncular cistern, c) no evidence of a structural cause of SAH other than IA by CT or MR brain imaging.

Exclusion Criteria

1. Fusiform-shaped unruptured IA of a major intracranial trunk artery or IA which is part of an arteriovenous malformation.
2. Family history of polycystic kidney disease, Ehlers Danlos Syndrome, Marfan's Syndrome, fibromuscular dysplasia, or Moya-Moya syndrome (abnormal proliferation of small intracranial vessels that results from primary occlusion of intracranial arteries and can lead to SAH and ICH).
3. Failure to obtain informed consent from patient and family.

• Primary Phenotype: Intracranial Aneurysm
• Aortic Aneurysm, Abdominal

• Principal Investigator
  • Joseph P. Broderick, MD. Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
• Institute
  • National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
• Funding Source
  • R0139512. National Institutes of Health, Bethesda, MD, USA.
• Genotyping Center
  • Johns Hopkins University Center for Inherited Disease Research (CIDR), Baltimore, MD, USA.
• Funding Source for CIDR Genotyping
  • HHSN268200782096C. NIH contract "High throughput genotyping for studying the genetic contributions to human disease". National Institutes of Health, Bethesda, MD, USA.
  • HHSN268201100011I. NIH contract "High throughput genotyping for studying the genetic contributions to human disease". National Institutes of Health, Bethesda, MD, USA.