Proceedings of the 24th International Stroke Genetics Consortium Workshop: Washington, DC, USA

Objective: To identify haematological traits with a causal role in the development of stroke and stroke subtypes. Background: Blood cells and coagulation factors have many important roles including oxygen transport, immune response, iron homeostasis, clearance of apoptotic cells and toxins, vascular and endothelial cell function, response to systemic stress, and haemostasis. A recent analysis found evidence of a causal effect of several blood cell traits on coronary heart disease and Type 2 diabetes, but the causal relevance of haematological traits for stroke and its subtypes has not been established. This information is critical to inform the development of novel treatments for stroke patients. Design/Methods: We conducted a literature review of genome-wide association studies of haematological traits and downloaded publicly available summary statistics from these studies and the MEGASTROKE consortium. Mendelian randomization analyses were used to examine whether haematological traits have a causal effect on the development of stroke and its subtypes in both European-only and trans-ethnic populations. A gene score constructed from independent genetic variants associated with each trait was used as an instrumental variable to obtain an estimate of the causal effect using the ratio, inverse-variance weighted, weighted median, and MR-Egger approaches. Results: The literature review identified 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells), 43 coagulation factors, and 3 markers of platelet function from 28 published GWAS, which included data from UK Biobank, INTERVAL, CHARGE Consortium, CARe Consortium, BioBank Japan Project, ARIC, Rotterdam Study, Framingham Heart Study, and other cohorts, involving over 350,000 individuals. Genetic associations with stroke and stroke subtypes were available in 67,162 cases and 454,450 controls. Preliminary analyses on a subset of traits showed that plateletcrit had a significant causal effect (p < 8.4746 × 10−4) on all stroke (AS), any ischaemic stroke (AIS), and cardioembolic stroke (CES) in both European-only and trans-ethnic populations; Factor VIII activity had a significant causal effect on AS, AIS, large-artery stroke (LAS), and CES in both populations; and von Willebrand Factor had a significant causal effect on AS and AIS in both populations and a marginally significant effect (p < 1 × 10−3) on CES in a trans-ethnic population. There were also suggestive causal associations of 27 of the blood cell traits on stroke and various subtypes; of activated partial thromboplastin time and Factor VII clotting activity with AS, AIS, and small vessel stroke (SVS); and of prothrombin time and collagen lag time with CES. Conclusions: Our preliminary analyses have so far identified one blood cell trait, 2 coagulation factors, and one marker of platelet function that exhibit evidence of a significant causal association with stroke and various subtypes of stroke, as well as numerous haematological traits that are marginally significant or suggestive of a causal effect. Further investigation of these traits could lead to the development of novel drug targets for the treatment and prevention of stroke.EU Horizon 2020 grant agreement No 667375 (CoSTREAM