We conducted a European-only and trans-ancestral genome-wide association meta-analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p=2.2E-8; OR=1.05[1.04-1.07]) and variants in an intron of COL4A1 (rs9521634, p-value=3.8E-8, OR=1.04[1.03-1.06]) and near DYRK1A (rs720470, p=6.1E-9; OR=1.05[1.03-1.07]) at genome-wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian Randomization we further show that genetic variation in the nitric oxide synthase (NOS) - nitric oxide (NO) pathway in part affects stroke risk via variation in blood pressure. This article is protected by copyright. All rights reserved.