We identified references for this Review by searching PubMed from January, 1970, to September, 2013, using combinations of the terms: “stroke”, “ischaemic”, “haemorrhagic”, “intracerebral hemorrhage”, “gene”, “mutation”, “polymorphism”, “association”, and “GWAS”. We restricted our search to articles published in English. We also found relevant papers by searching authors' personal communications with collaborators from across the International Stroke Genetics Consortium. We selected
ReviewCurrent concepts and clinical applications of stroke genetics
Introduction
Despite substantial progress in prevention and treatment, stroke remains the third greatest cause of death globally and is a leading factor in disability and age-related cognitive decline and dementia.1 Genetic investigation of individuals who have had a stroke is a promising approach for identification of novel biological mechanisms that underlie the development of cerebrovascular disease.2 Discovery of new targets could aid development of preventive strategies and acute treatments. Fuelled by high-throughput genotyping technologies, novel analytical methods, and large-scale collaborations, the search for stroke genes has entered a promising phase. The list of genetic variants with a robustly proven effect on stroke risk has grown beyond the rare mutations that underlie familial syndromes to include common variants that—albeit with fairly small effects—affect the usual forms of stroke encountered by neurologists in everyday clinical practice.
Accelerated identification of susceptibility genes and biological pathways has transformed research in complex traits such as blood pressure3 and lipid metabolism,4 diabetes,5 coronary artery disease,6 and disorders unrelated to vascular disease, such as schizophrenia.7 Dozens of genetic loci have been identified in these disorders by studying up to 100 000 patients and controls, and progress suggests that the yield of novel genetic loci will increase steadily once sample sizes grow beyond ten times the original study size needed to identify the first genetic locus.8 The pace of these advances suggests that stroke genetics is now at a stage whereby accelerated identification of susceptibility genes and biological pathways can take place. Owing to the efforts of the International Stroke Genetics Consortium9 and its METASTROKE Collaboration,10 stroke is less than halfway through the process of achieving comparable sample sizes; completion of the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN) Study11 at the end of 2014 will represent an important milestone in achieving this goal.
In this Review, we aim to interpret the most recent discoveries in stroke genetics and discuss possible future breakthroughs. The association between known genetic variants and specific stroke subtypes highlights the idea—long-recognised by neurologists—that stroke is a syndrome rather than one disease12 and that accurate, biologically informed identification of stroke subtypes is paramount to the success of stroke genetics. Application of classification schemes that categorise strokes on the basis of their known or presumed underlying biological mechanism has been fundamental to genetic discovery. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification system has been the main methodological approach used for ischaemic stroke, categorising patients with this disorder into large-vessel or small-vessel stroke, cardioembolic stroke, other causes of stroke, or undetermined causes.13 Similarly, the lobar or non-lobar classification14 has been applied to intracerebral haemorrhage. Looking ahead, large collaborations assembled for genetic studies in stroke provide an opportunity to implement, test, and refine novel, more detailed, and reliable classification schemes, such as the Causative Classification of Stroke system.15
Through comprehensive assessment of the role of common and rare genetic variation across the entire genome, the findings of genome-wide association studies,16 whole-genome studies,17 and whole-exome sequencing studies18 expose previously unsuspected biological mechanisms in stroke, which offer a much-needed first step in the search for novel biological targets for therapeutic intervention.19 At the bedside, testing for genetic variation opens up the possibility of tailoring treatment to the genetic make-up of every patient, by stratification, for example, of individuals on the basis of genetically ascertained responses to pharmacotherapy and by incorporation of predictive information related to risk of stroke and adverse events to specific drugs.20 Finally, genetic discoveries could soon refine the way stroke is regarded, as we envision a future in which stroke subtyping incorporates genetic information along with clinical and neuroimaging characteristics.
Section snippets
Methodological advances
Genotyping technologies continue to evolve rapidly, as do study designs and statistical methods used to process the resulting data, meaning that full understanding of these approaches requires familiarity with terms commonly used in medical population genetics (panel). A simple way to understand the reach of a genotyping strategy is to consider two dimensions: coverage and depth.22 Coverage might be the entire genome, a specific set of genes, or only one gene or genomic region, whereas depth
Statistical considerations
Increasing the sample size of genome-wide association studies can escalate identification of susceptibility loci, as experience with other complex traits shows (table 1). The large sample sizes included by international stroke consortia suggest that the discovery pace of stroke-related susceptibility loci is likely to accelerate in the near future.8 Beyond identification of new risk loci through single-variant association testing, several new statistical approaches are gaining acceptance
Genetics of ischaemic stroke
Early evidence supporting a role of genetic variation in patients with ischaemic stroke emerged from twin studies undertaken in the 1990s; a five times higher risk was reported in monozygotic twins compared with dizygotic twins or siblings.39 Findings from subsequent twin and family history studies corroborated these results40 and indicated that genetic predisposition to ischaemic stroke differs according to age and stroke subtype. The genetic component is more prevalent in large-vessel
Genetics of intracerebral haemorrhage
Important genetic discoveries have been described for haemorrhagic stroke. Here, we focus on intracerebral haemorrhage, which is the most frequent type of haemorrhagic stroke; for genetic findings with respect to intracranial aneurysms, we refer the reader to other published articles.85, 86 Similar to ischaemic stroke, recognition of the biological heterogeneity that underlies distinct subtypes of intracerebral haemorrhage—with implementation of phenotyping strategies reflecting these
Endophenotypes
Endophenotypes are measurable traits that are postulated to lie along the causal pathway from genetic variation to disease expression.111 Study of endophenotypes can facilitate the identification of genetic risk factors, because they are more frequent and easier to quantify than the final outcome of interest, and they sometimes yield continuous distributions that allow implementation of powerful statistical analysis.
An important imaging endophenotype for stroke is white-matter hyperintensities
Clinical applications
Recognition of individuals—and families—carrying rare mutations that cause mendelian diseases with stroke as a phenotypic manifestation remains an important consideration for clinicians.120 Fabry's disease represents a relevant example, and young patients with ischaemic stroke of undetermined cause should be screened routinely for this disorder. In general, mendelian disorders can be recognised by their familial aggregation, relatively young age of onset, more severe clinical course, and higher
Conclusions and future directions
For complex traits such as stroke, we now know that an escalation in study sample size is related to the discovery of susceptibility loci in a linear fashion;134 moreover, this relation could be exponential for some traits. The priority for genetic research in stroke in the near future is to improve the framework needed to expand collaboration networks, particularly in Asia, Africa, and Latin America. A key development will be to refine collaboration rules to fit the expectations of all
Search strategy and selection criteria
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Targeted re-sequencing in pediatric and perinatal stroke
2020, European Journal of Medical GeneticsAQP4 tag SNPs in patients with intracerebral hemorrhage in Greek and Polish population
2019, Neuroscience LettersCitation Excerpt :A blend of genetic, as well as of environmental factors confers susceptibility to the ICH [3]. Regarding the genetic aspect, a few genetic variations have been related to the risk of primary ICH [4–11]. Moreover, there is some evidence for an implication of genetic loci to the functional outcome and the recovery after ICH [12].
Intracerebral Hemorrhage Genetics
2022, GenesStroke and Etiopathogenesis: What Is Known?
2022, Genes
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Contributed equally