Cerebrovascular disease is the third leading cause of death in the United States and about one-quarter of cerebrovascular deaths due to ruptured intracranial aneurysms (IA). Of those who survive rupture of an IA, more than half are left with neurological deficits. In contrast, the morbidity of elective surgery and treatment before rupture is very low (1-2%), so that early intervention could be extremely valuable. Several reports suggest that some IAs are familial and probably genetic. Identification of family members at risk for developing IA will allow concentration of diagnostic effort on a small number of high-risk individuals and assist early identification of IAs. Characterization of one or more genes that predispose individuals to developing IA will significantly increase the effectiveness of this diagnostic effort.
The aim of this study is to use linkage analysis to identify one or more loci that are linked to IA in families. For this purpose, 1150 Finish families were initially ascertained on the basis of having an individual with proven IA. 85 families were identified with a second member who had IA and had no other known predisposing condition. Magnetic resonance angiography (MRA) was carried out in 531 asymptomatic first degree relatives of the probands. This effort resulted in sampling of DNA from 49 affected sibling pairs (ASPs) in a total of 24 families. DNA samples are available on all examined individuals. In this study, the investigators propose to: collect samples from an additional 35-40 affected sib pairs; 2) perform affected sib-pair linkage analysis in two phases, I) first with currently available sib pairs and II) with all 84-89 affected sib pairs in regions identified as suggestive of linkage from phase I; 3) collect information on a sample of families with one affected member; 4) fit genetic models using the data collected in 3 and the existing data on the 85 families and then perform parametric linkage analysis; 5) continue to collect genealogical information on the 85 families that may assist in subsequent fine-mapping efforts.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Jacobs, Tom P
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Wayne State University
Schools of Medicine
United States
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Helgadottir, Anna; Gretarsdottir, Solveig; Thorleifsson, Gudmar et al. (2012) Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol 60:722-9
He, Chunsheng; Weeks, Daniel E; Buyske, Steven et al. (2011) Enhanced genetic maps from family-based disease studies: population-specific comparisons. BMC Med Genet 12:15
Gretarsdottir, Solveig; Baas, Annette F; Thorleifsson, Gudmar et al. (2010) Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat Genet 42:692-7
Tromp, G; Kuivaniemi, H (2009) Developments in genomics to improve understanding, diagnosis and management of aneurysms and peripheral artery disease. Eur J Vasc Endovasc Surg 38:676-82
Helgadottir, Anna; Thorleifsson, Gudmar; Magnusson, Kristinn P et al. (2008) The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 40:217-24
Weinsheimer, Shantel; Lenk, Guy M; van der Voet, Monique et al. (2007) Integration of expression profiles and genetic mapping data to identify candidate genes in intracranial aneurysm. Physiol Genomics 32:45-57
Weinsheimer, Shantel; Goddard, Katrina A B; Parrado, Antonio R et al. (2007) Association of kallikrein gene polymorphisms with intracranial aneurysms. Stroke 38:2670-6
van der Voet, Monique; Olson, Jane M; Kuivaniemi, Helena et al. (2004) Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3. Am J Hum Genet 74:564-71
Wills, Shannon; Ronkainen, Antti; van der Voet, Monique et al. (2003) Familial intracranial aneurysms: an analysis of 346 multiplex Finnish families. Stroke 34:1370-4
Kuivaniemi, Helena; Yoon, Sungpil; Shibamura, Hidenori et al. (2002) Primer-extension preamplified DNA is a reliable template for genotyping. Clin Chem 48:1601-4

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