P.O., Box 208082
New Haven, CT 06520-8082
For the last 15 years, we have been ascertaining patients and families with intracranial aneurysm (IA) to lay the groundwork for genetic studies of this deadly disease. Up to 5% of the population is affected with IA by age 60 (Fig. 1). While, brain bleeding (most often due to subarachnoid hemorrhage-SAH) is not common among this group, affecting 1 in 10,000 people, SAH is nonetheless highly morbid, with 40-50% of individuals not surviving the initial bleed. Having now accumulated one of the largest collections of DNAs in the world, my lab has undertaken wide-ranging studies of the genetics of IA, focusing both on common and rare susceptibility alleles. The ultimate aim of this work is to identify novel avenues for early diagnosis and effect treatment of this potentially devastating disease.
In order to identify rare IA susceptibility genes, we recruited difficult-to-find, multigenerational IA families. Through genome wide linkage analyses, we have now identified and published 3 loci that segregate as dominant Mendelian forms of IA (AJHG 2005 ;76(1):172-9; Stroke 2006 ;37(4):1021-7). Mutational analysis of the genes located within these linked intervals is currently underway. Even though these rare alleles are not expected to explain the majority of IA disease risk, they promise to be crucial to providing the first insights into IA pathophysiology.
In addition to the study of rare alleles, we have also focused on identification of common variants through a whole genome association (WGA) study in collaboration with Dr. Richard Lifton. This effort which is through a large international consortium includes groups from Helsinki and Kuopio in Finland, Utrecht in the Netherlands and Tokai in Japan. Over the past several months, we have consolidated a sample of over 10,000 individuals (2,800 cases vs 7,500 controls) from Finland, the Netherlands, Japan and Germany, and completed genome wide genotyping using this sample. Our preliminary findings already point to immediate opportunities for clinical applications. This study promises to provide unique insights into the molecular pathophysiology of aneurysms, leading not only to pre-clinical diagnosis but also to novel therapeutic approaches that will have major impact on the disease.
These studies are funded by a R01 from NIH (NINDS primary/NHLB secondary), funds from the Yale Center for Human Genetics and Genomics and the Yale Neurogenetics Program.