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(Stroke. 2008;39:2166.)
© 2008 American Heart Association, Inc.

Topical Review

The Genetic Architecture of Intracerebral Hemorrhage

Natalia S. Rost, MD; Steven M. Greenberg, MD, PhD Jonathan Rosand, MD, MSc

From the Department of Neurology, and Hemorrhagic Stroke Research Program (N.S.R., S.M.G., J.R.), Center for Human Genetic Research (N.S.R., J.R.), Massachusetts General Hospital, Boston, Mass; and Broad Institute of MIT and Harvard (N.S.R., J.R.), Cambridge, Mass.

Correspondence to Jonathan Rosand, MD, MSc, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, CPZN 6818, Boston MA 02114. E-mail jrosand{at}partners.org

Robert Hegele MD Martin Dichgans MD Section Editors:

Abstract

Background and Purpose— Intracerebral hemorrhage (ICH), the acute manifestation of a common progressive cerebrovascular disease of the elderly, is the most fatal and least treatable form of stroke. There is a desperate need for ICH-specific therapeutics and effective primary prevention strategies, a need that is certain to grow with the aging of the population. Data point to a sizable genetic component to ICH susceptibility. Identification of ICH-related genes therefore holds promise for identifying novel biological targets for ICH prevention. This review focuses on evidence for a genetic contribution to ICH, delineates approaches to genetic studies of ICH, and explores foundations for their future applications.

Summary of Review— ICH occurs both sporadically and as part of familial syndromes. Monogenic disorders associated with ICH or microscopic bleeding, such as hereditary cerebral amyloid angiopathy, CADASIL, and collagen type IV A1–associated vasculopathy, demonstrate the potent effect of rare mutations. Dissecting the more complex genetics of sporadic ICH, however, will likely require defining multiple common DNA variants with weaker effects. Advances in high-throughput genotyping technology, computational and analytic methodologies, and large-scale collaborative efforts have already led to the identification of new genetic risk factors for dozens of common diseases. Such whole-genome association studies are being undertaken in sporadic ICH.

Conclusions— Investigations of genetic risk factors for sporadic ICH have thus far been limited to candidate gene polymorphisms. Genome-wide association studies currently hold the greatest hope for robust discovery of ICH genes, which can generate novel insights into ICH biology and strategies for prevention.

Key Words: genetics • association • intracerebral hemorrhage • stroke prevention • review