ADAMTS12, a new candidate gene for pediatric stroke

We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene familyADAMTS2(rs469568,p= 8x10(-6)) andADAMTS12(rs1364044,p= 2.9x10(-6)). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs inADAMTS2and six inADAMTS12potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed theADAMTS12variant rs77581578 to be significantly under-transmitted (p= 6.26x10(-3)) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis ofADAMTS12detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such asADAMTS13are involved in thromboembolic disease process. Here, we provide further evidence forADAMTS12to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.