Search for intracranial aneurysm susceptibility gene(s) using Finnish families

Abstract

Background: Cerebrovascular disease is the third leading cause of death in the United States, and about one-fourth of cerebrovascular deaths are attributed to ruptured intracranial aneurysms (IA). Epidemiological evidence suggests that IAs cluster in families, and are therefore probably genetic. Identification of individuals at risk for developing IAs by genetic tests will allow concentration of diagnostic imaging on high-risk individuals. We used model-free linkage analysis based on allele sharing with a two-stage design for a genome-wide scan to identify chromosomal regions that may harbor IA loci.

Methods: We previously estimated sibling relative risk in the Finnish population at between 9 and 16, and proceeded with a genome-wide scan for loci predisposing to IA. In 85 Finnish families with two or more affected members, 48 affected sibling pairs (ASPs) were available for our genetic study. Power calculations indicated that 48 ASPs were adequate to identify chromosomal regions likely to harbor predisposing genes and that a liberal stage I lod score threshold of 0.8 provided a reasonable balance between detection of false positive regions and failure to detect real loci with moderate effect.

Results: Seven chromosomal regions exceeded the stage I lod score threshold of 0.8 and five exceeded 1.0. The most significant region, on chromosome 19q, had a maximum multipoint lod score (MLS) of 2.6.

Conclusions: Our study provides evidence for the locations of genes predisposing to IA. Further studies are necessary to elucidate the genes and their role in the pathophysiology of IA, and to design genetic tests.

Figure 1

FIA Pedigrees. The genome scan was performed with the 48 of 49 affected sibling pairs from the 24 sibships since one of the pairs in family 21 was determined to be a non-sib pair. GT indicates that DNA from the corresponding individual was genotyped. Symbols are defined in the figure: DSA denotes digital subtractive angiography; MRA denotes magnetic resonance angiography.

Figure 2

Chromosome 19 multipoint lod score versus genetic distance (cM). Also indicated below the cM scale are the polymorphic markers.