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Study Description

The goal of this study is to identify the genes underlying the risk of intracranial aneurysm (IA). The FIA Study initially recruited families appropriate for linkage analysis. Therefore, the recruitment focus was not only on probands with a family history of IA but also required that biological samples be obtained for at least two affected family members. Family members underwent detailed interviews for medical, social and family history, and provided blood samples for DNA extraction. Over 400 multiplex IA families were recruited and enrolled.

The whole exome sequencing project aims to identify novel and rare (in the general population) genetic variants that are enriched in seven extended multiplex families with a strong familial aggregation of intracranial aneurysms.

  • Study Weblink: FIAII
  • Study Type: Family
  • dbGaP estimated ancestry components using GRAF-pop
  • Number of study subjects that have individual level data available through Authorized Access: 45

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

A highly structured diagnostic algorithm was used to phenotype FIA study subjects. All medical records and imaging studies, as well as a screening interview about aneurysm history, were obtained from individuals with a reported history of IA, SAH, or intra cerebral hemorrhage. These data were reviewed by a Verification Committee consisting of study neurologists at the University of Cincinnati and the Mayo Clinic. Two neurologists independently reviewed the records and decided if the subject met all the inclusion and exclusion criteria. In cases of disagreement between the two initial reviewers, a third neurologist was used to resolve the case diagnosis.

First degree relatives of an individual with an IA (parent, sibling or child) who also had risk factors increasing the likelihood that they might have an unruptured IA (i.e. age of 30 years or older, history of smoking or hypertension) were offered a free study MRA to detect an unruptured IA. All magnetic resonance angiography (MRA) and computed tomography angiography (CTA) scans were reviewed by two neuroradiologists at the Mayo Clinic to determine presence or absence as well as size and location of an IA. For any differences, a consensus meeting was held by the two neuroradiologists. Rigorous phenotype classification was performed for each subject.

Definite: Medical records document aneurysm on angiogram, operative report, autopsy, or a non-invasive imaging report (MRA, CTA) demonstrates an IA measuring greater than 7mm.

Probable: Death certificate mentions probable intracranial aneurysm without supporting documentation or autopsy. Death certificate mentions subarachnoid hemorrhage without mention of aneurysm and a phone screen is consistent with ruptured IA (severe headache or altered level of consciousness) rapidly leading to death. An MRA documents an IA that is less than 7 mm but greater than 3 mm.

Possible: Non-invasive imaging report documents an aneurysm measuring between 2 and 3 mm. Subarachnoid hemorrhage was noted on death certificate, without any supporting documentation, autopsy or recording of headache or altered LOC on phone screen. Death certificate lists 'aneurysm' without specifying cerebral location or accompanying SAH.

Not an Affected Case: There is no supporting information for a possible IA

For the whole exome sequencing project, all families were reviewed and a set of 7 densely affected IA families were selected for whole exome sequencing. The families chosen had the largest number of definite IA cases. Each family had at least 4 definite IA cases with whole blood DNA available. In addition, in some families 1-2 unaffected individuals were also selected for WES. These unaffected individuals were older (past likely age of IA risk within the family) and had a previous MRA that did not provide any evidence of an unruptured IA. All families included in the WES were of Caucasian ancestry.

Individuals were excluded from this study if the IA was of a fusiform shape and unruptured; if the IA was part of an arteriovenous malformation; or if there was a family history of polycystic kidney disease, Marfan's Syndrome, Ehlers-Danlos Syndrome, fibromuscular dysplasia, or Moya-Moya syndrome.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Exome Sequencing Illumina HiSeq 2000 N/A N/A
Whole Exome Sequencing Illumina TruSeq SBS Kit v3-HS N/A N/A
Whole Exome Sequencing Agilent SureSelectXT Human All Exon 50Mb N/A N/A
Study History

The goal of this study is to identify the genes underlying the risk of intracranial aneurysm (IA). The FIA Study initially recruited families appropriate for linkage analysis. Therefore, the recruitment focus was not only on probands with a family history of IA but also required that biological samples be obtained for at least two affected family members. Family members underwent detailed interviews for medical, social and family history, and provided blood samples for DNA extraction. Over 400 multiplex IA families were recruited and enrolled.

As part of the study, samples from these families have been used in linkage analyses using both microsatellite markers and SNPs. One affected individual per family was selected as part of a case - control sample. For this analysis, all families were reviewed and seven that had the strongest family history of IA and the largest number of DNA samples from affected individuals were selected.

Selected publications
Diseases/Traits Related to Study (MESH terms)
Authorized Data Access Requests
Study Attribution