The International Stroke Genetics Consortium and the Wellcome Trust Case Control Consortium 2 published the largest genome-wide association study (GWAS) for ischaemic stroke carried out to date [
1]. Ischaemic stroke is the second leading cause of death and the major cause of long-term disability worldwide [
2]. The risk for stroke increases with age and with risk factors like cigarette smoking, obesity, physical inactivity, hypertension, atherosclerosis, atrial fibrillation, a family history of stroke or a previous stroke or TIA [
3]. However, not all brain infarcts are alike. Rather, they have multiple, sometimes competing, underlying aetiologies and subtypes. Five stroke subtypes were defined according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification [
4], using clinical and diagnostic features: 1) large-artery atherosclerosis (large vessel disease, LVD), 2) cardioembolism (CE), 3) small-vessel occlusion (small vessel disease, SVD), 4) stroke of other determined etiology (rare underlying causes such as arterial dissection, inherited diseases of the coagulation system or vasculitis), and 5) stroke of undetermined etiology. Patients with LVD, SVD and CE stroke subtypes have distinct symptoms, distinct risk profiles and subtype-specific risks for recurrent events or events in first degree relatives [
5,
6]. Stroke risk modification and stroke prevention remain major items in health care. Primary and secondary stroke prevention strategies differ according to stroke subtype, for example, anticoagulation for cardioembolic strokes, platelet inhibition for large vessel disease, antihypertensive treatment and statins for most subtypes [
6].
In some patients, despite extensive search, no underlying causes are found and increasingly, we identify overlapping etiologies, such as the combination of large vessel (carotid) arteriosclerosis and atrial fibrillation as a potential source of a cardioembolism. Even the subgroup LVD-stroke is heterogeneous and far from being a simple homogeneous phenotype. Many readers might feel that LVD mainly refers to carotid bifurcation occlusive disease. However, thrombogenic aortic disease, vertebrobasilar occlusive disease (which appears to be different from carotid disease), distal carotid stenosis and intracranial occlusive disease (more frequent among Asians and Afro-Americans) are all part of the LVD-definition.