Study protocol

The Familial Intracranial Aneurysm (FIA) study protocol

Joseph P Broderick¹ , Laura R Sauerbeck¹ , Tatiana Foroud² , John Huston III³ , Nathan Pankratz² , Irene Meissner⁴ and Robert D Brown Jr⁴

¹Department of Neurology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0525, USA

²Medical & Molecular Genetics, Indiana University, 975 West Walnut St., IB 130, Indianapolis, IN 46202-5251, USA

³Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

⁴Division of Cerebrovascular Disease and Department of Neurology, Mayo Clinic, 200, First Street SW, Rochester, MN 55905, USA

author email corresponding author email

BMC Medical Genetics 2005, 6:17doi:10.1186/1471-2350-6-17

Published:	26 April 2005

Abstract

Background

Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 20,000 people per year in the U.S. annually and nearly half of the affected persons are dead within the first 30 days. Survivors of ruptured IAs are often left with substantial disability. Thus, primary prevention of aneurysm formation and rupture is of paramount importance. Prior studies indicate that genetic factors are important in the formation and rupture of IAs. The long-term goal of the Familial Intracranial Aneurysm (FIA) Study is to identify genes that underlie the development and rupture of intracranial aneurysms (IA).

Methods/Design

The FIA Study includes 26 clinical centers which have extensive experience in the clinical management and imaging of intracerebral aneurysms. 475 families with affected sib pairs or with multiple affected relatives will be enrolled through retrospective and prospective screening of potential subjects with an IA. After giving informed consent, the proband or their spokesperson invites other family members to participate. Each participant is interviewed using a standardized questionnaire which covers medical history, social history and demographic information. In addition blood is drawn from each participant for DNA isolation and immortalization of lymphocytes. High- risk family members without a previously diagnosed IA undergo magnetic resonance angiography (MRA) to identify asymptomatic unruptured aneurysms. A 10 cM genome screen will be performed to identify FIA susceptibility loci. Due to the significant mortality of affected individuals, novel approaches are employed to reconstruct the genotype of critical deceased individuals. These include the intensive recruitment of the spouse and children of deceased, affected individuals.

Discussion

A successful, adequately-powered genetic linkage study of IA is challenging given the very high, early mortality of ruptured IA. Design features in the FIA Study that address this challenge include recruitment at a large number of highly active clinical centers, comprehensive screening and recruitment techniques, non-invasive vascular imaging of high-risk subjects, genome reconstruction of dead affected individuals using marker data from closely related family members, and inclusion of environmental covariates in the statistical analysis.