Genetics of Spontaneous Intracerebral Hemorrhage

• cerebral hemorrhage
• genetics
• genetics, population
• genome-wide association study
• polymorphism, single nucleotide

The epidemiology of spontaneous intracerebral hemorrhage (ICH) has rapidly progressed in the past few decades, with important genetic and nongenetic discoveries.¹ Hypertension has long been associated with ICH, and evidence now demonstrates that untreated hypertension produces substantial increases in risk of this condition.^2,3 Unlike cardiovascular disease, cholesterol is inversely associated with ICH, with low levels of total and low-density lipoprotein cholesterol having an association with increased risk.^4,5 Along these lines, the SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)⁶ demonstrated that in secondary prevention of ischemic stroke, statin use was associated with a small increase in risk of ICH although large meta-analyses did not confirm this correlation in the general population.⁷ Moderate alcohol consumption has consistently been identified as associated with a lower ICH risk whereas heavy alcohol consumption has been found to associate with an elevated risk of this condition.⁸ Anticoagulant treatment, largely in relationship to warfarin use, has also been consistently associated with ICH risk with a particular predilection for cerebellar ICH.^9,10 Finally, cerebral amyloid angiopathy (CAA), first recognized as an ICH mechanism in the 1990s, is a common feature of lobar hemorrhages.¹¹

Although these risk factors explain an important proportion of the variance in ICH risk, a significant portion of this variation remains unexplained. In addition, in the absence of proven acute treatments for ICH, novel targets for therapeutic interventions are urgently needed. Population genetics can contribute to solve these 2 unanswered questions as heritability estimates based on genome-wide data from unrelated individuals indicate that up to 30% of ICH risk can be explained by common and rare genetic variation.¹² Furthermore, through studies that combine environmental and genetic risk factors, genomic analysis can also help us understand how individual susceptibility …