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Introduction Genetic influences upon ischemic stroke risk are supported by the trait’s familial aggregation, higher concordance among monozygotic than dizygotic twins, and the high heritability of intermediate phenotypes such as carotid intima-media thickness. In spite of this evidence, genome-wide association studies (GWAS) have detected few replicable genetic risk factors for ischemic stroke, potentially due to aetiological heterogeneity of this trait. Hypothesis We first assessed the hypothesis that common ischemic stroke subtypes differ in their heritability, defined as the proportion of observed phenotypic variation attributable to genetic variation. The second hypothesis was that GWAS may detect stronger and more replicable genetic associations for distinct stroke subtypes with high heritability, rather than the broad ischemic stroke diagnosis. Methods An Australian, European-ancestry sample of 1230 ischemic stroke cases and 1280 population controls was genotyped for a genome wide association study using the Illumina 610-Quad array. Ischemic stroke subtypes were assigned using TOAST criteria. The proportion of case-control variation attributable to genome wide genetic variation was estimated using a published approach based on linear mixed models. Genome wide association analyses incorporating approximately 2.5 million genotyped and imputed SNPs were subsequently performed using a one-degree of freedom trend test assuming an additive effect of allele dosage. Results Significant evidence for a genetic contribution to ischemic stroke risk was detected ( h 2 =0.39, SE=0.15, p-value = 0.0009), but this was higher and more significant for the large artery atherosclerosis (LAA) subtype ( h 2 =0.66, SE=0.21, p-value = 0.0001). The genetic contributions to small vessel disease and cardioembolic stroke were less significant than for overall ischemic stroke. Genome wide association analyses including 421 LAA cases and 1244 controls detected a novel LAA susceptibility locus on chromosome 6p21.1 (two SNPs with P <5×10 -8 ). The 6p21.1 locus showed markedly diminished association with the broader ischemic stroke phenotype. Conclusions In conclusion, this study detected higher heritability of large artery atherosclerotic stroke than cardioembolic stroke, small vessel disease or broad ischemic stroke. It suggests a genetic risk locus for large artery atherosclerosis on chromosome 6p21.1 and supports the analysis of aetiological subtypes to better identify genetic risk alleles for ischemic stroke.