Advances in Genomic Analysis of Stroke

Abstract

Abstract-As a result of technological advances, the genomic analysis of stroke has shifted from candidate gene association studies to genome-wide association studies (GWAS). Agnostic GWAS evaluate up to 90% of common genetic variation in a single experiment, creating an improved framework for identifying novel genetic leads for biochemical and cellular mechanisms underlying stroke. Given the ubiquity of the GWAS approach, it has become essential for stroke researchers and clinicians to be able to interpret GWAS results. Thus, we review the basic elements of design, methods, presentation, and interpretation of GWAS in the context of stroke research. In 8 recent stroke GWAS reports, no single locus has been identified in 2 GWAS at a genome-wide level of significance. Additionally, no significant association signal between stroke and a locus with previous evidence from candidate gene studies of stroke has been identified yet. Some caveats of the approach and future directions for stroke genomics are discussed, including the use of intermediate phenotypes, Mendelian randomization, phenomics, and deep resequencing. Intelligent, appropriately powered, multidisciplinary studies incorporating knowledge from clinical medicine, epidemiology, genetics, and molecular biology will be required to fully characterize the genomic contributors to stroke. (Stroke. 2010;41:825-832.)

The APOE E4 Allele Confers Increased Risk of Ischemic Stroke Among Greek Carriers

“…Firstly, as ischemic stroke may be caused by occlusion (~80% of the cases) or hemorrhage (~20% of the cases) of cerebral blood vessels, several gene polymorphisms with a potential functional effect on blood coagulation proteins have been investigated in the last decade as potential risk factors for IS or CHD, with inconclusive results [28][29][30]. Similarly, a large number of published genome-wide association studies (GWAS) investigating thousands of single nucleotide polymorphisms (SNPs) across the human genome have failed to identify DNA sequence variants which, even when combined, are in a position to provide clinically useful and robust genotype-phenotype associations [26][27][28][29]. On the one hand, the results of these studies confirm the complex and multifactorial basis of cerebro-and cardiovascular disease in general, and more specifically of IS and CHD, while at the same time they exhibit considerable phenotypic variations in patient selection and study design.…”

Advances in biomarker for stroke patients: from marker to regulator

“…glutamate, GABA [16,17] Etiologic diagnosis of ischemic stroke, e.g., atherosclerotic (inflammatory markers) vs. [53]. However, genomewide association studies failed to reproduce the positive results obtained from previous stud ies [54] or the clinical usefulness was very low [55]. For exam ple, the hazard ratio and population attributable risk of hy pertension to ischemic stroke is 2.0 and 26%, respectively.…”

Treatment Targets in Intracerebral Hemorrhage

“…Researchers are now able to conduct accurate and efficient analyses across the entire genome of a study subject. Specifically, the genome-wide association study (GWAS) represents an experimental framework that can rapidly and efficiently identify novel pathogenic mechanisms, and can confirm a role for previously known mechanisms [34].…”