Research in context
Evidence before this study
We searched PubMed with the search terms “stroke” and “genome wide association study” for reports published before Oct 19, 2015. We only included peer-reviewed reports in English. Compared with the rapid pace of genetic discovery for other common disorders, only four loci (PITX2, HDAC9, ZFHX3, and 12q24.2) have been convincingly implicated by genome-wide association studies (GWAS) in ischaemic stroke. GWAS of stroke have been limited by small sample sizes and concerns about phenotypic heterogeneity.
Added value of this study
To our knowledge, the National Institute of Neurological Disorders and Stroke (NINDS)-Stroke Genetics Network (SiGN) project is the largest and most comprehensive study of ischaemic stroke so far. Discovery analyses were done in 16 851 cases and 32 473 controls and findings were followed up in an additional 20 941 cases and 364 736 controls. Furthermore, the project implemented the Causative Classification of Stroke (CCS) system to subtype cases and generated a rich phenotypic database. Trial of Org 10 172 in Acute Stroke Treatment (TOAST)-based subtypes were also available, allowing for the first ever analysis of the genetic overlap between TOAST and CCS subtypes.
Implications of all the available evidence
Our data show that increasing sample size and applying a standardised subtyping method can reveal additional information about the underlying genetic architecture of stroke. Because we had access to phenotype information generated by two different subtyping methods, we also showed that there is moderate to strong genetic correlation between the CCS and TOAST subtyping methods, suggesting that future studies might benefit from liberal inclusion of cases, regardless of subtyping approach. Also, our results show that all discovered loci, including the 12q24.12 locus, which was previously implicated in all ischaemic stroke, are specific to a single subtype, suggesting that these subtypes will have at least partly distinct genetic signatures. Because of the subtype-specificity of genetic associations in stroke, substantially larger samples of stroke subtypes will probably be needed to expand the number of identified stroke loci to that of other common diseases.