Neurovascular Disorders

The second arm of Neurogenetics study in the lab is identifying genetic factors that underlie intracranial aneurysm. For this purpose, we focus on two different approaches: (1) Genome-wide association studies (GWAS) of intracranial aneurysm that utilize common variants based on the analysis of over 40,000 subjects from Europe, Japan and North America. We are also interested in post-GWAS analysis that combines GWAS signal and other biological information (such as gene expression data, eQTL, DNA methylation) by using statistical methods to get a better understanding of the pathogenesis of intracranial aneurysm. (2) The other genetic approach for complex diseases is the 'common disease - rare variant' hypothesis. It states that common complex diseases reflect the aggregation of multiple "large-effect" rare variants, which are found in less than 1% of the population. Whole exome sequencing (WES) has been a cost effective and an important tool to detect rare variants as well as common variants in protein coding regions of the human genome.

We apply GWAS and WES technologies to a large cohort of familial and sporadic cases to understand the effects of both common and rare variants in the pathophysiology of intracranial aneurysms. Using these approaches we have previously reported on the identification of aneurysm susceptibility loci/ genes (Nahed BV, Seker A, et al. 2005; Ozturk AK, Nahed BV, et al., 2006; Nahed BV, Bydon M, et al., 2007; Bilguvar K, Yasuno K, et al., 2008; Yasuno K, Bilguvar K, et al., 2010; Gaál EI, Salo P, et al., 2012). Studies are currently underway with candidate genes in both, in vitro and in vivo animal model systems to confirm the functional validity of the identified candidates in causing intracranial aneurysms.

Besides IA, another major focus of my lab has been the study of molecular genetics and biology of cerebral cavernous malformations (CCM) in collaboration with Angeliki Louvi, PhD.

CCM is a major form of hemorrhagic stroke, affecting nearly 0.5% of the population. CCMs are abnormally dilated vascular channels in the brain that can lead to bleeding or seizures. Our work over the past 15 years on this disease have led to several seminal contributions, resulting in over 20 publications in peer-reviewed journals and over 40 national and international presentations. We localized the first gene that causes CCM on chromosome 7q (PNAS 1995 92(14):6620-4) in Hispanic-Americans (N Engl J Med. 1996 ;334(15):946-51) that was followed by large scale mutational analysis of CCM genes (J Neurosurg 2003; 99(1):38-43) and molecular and biological studies to understand their biological function (PNAS 2002; 99(16):10677-82, Neurosurg 2004; 54(4):943-9, Stroke 2006; 37(2):518-23, Neurosurg 62(4):930-8, 2008, Stroke 2008). This body of work spanning the past 20 years, is representative of our general philosophy of identification of disease genes followed by the dissection of disease biology. This work now places us in a unique position, for the first time, to attempt to develop novel therapies for CCM.