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Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations (P

Background— Recently, we reported a gene network of ADAMTS (A Disintegrin-like and Metalloprotease with Thrombospondin motifs) genes as central component of the genetic risk contributing to pediatric stroke. ADAMTS13 is a prime example for such a key component as it cleaves von Willebrand factor multimers, reduces platelet adhesion and aggregation, and downregulates thrombus formation and inflammation. Methods and Results— We characterized the genetic architecture of ADAMTS13 through targeted next-generation sequencing of 48 affected children and their unaffected siblings and identified in total 241 variants (single nucleotide polymorphisms or insertions/deletions) in the ADAMTS13 gene. From these, based on significance in the sibship disequilibrium test ( P ADAMTS13 gene for genotyping in 270 trios and subsequent association analyses. Transmission disequilibrium testing was performed for affection status and ADAMTS13 activity levels using PLINK and FBAT, respectively. Ten single nucleotide polymorphisms were significantly associated with pediatric stroke ( P P P =0.0004 and P =0.0092). The resulting protective haplotype H1.1. (T:U 95.5: 144.4; P =0.0016) is associated with increased ADAMTS13 levels (age-adjusted P =0.0108). Haplotype association using a sliding window approach assigns this association to the ADAMTS13 von Willebrand factor–binding domain ( P =1.2×10 −4 ). Conclusions— Our data provide a link between the genetic architecture of ADAMTS13 , ADAMTS13 levels, and stroke susceptibility. Altogether, these studies render ADAMTS13 an attractive candidate for functional studies and may contribute to personalized diagnosis and treatment options in future.

Pediatric stroke is a rare but highly penetrant disease with a strong genetic background. Although there are an increasing number of genome-wide association studies (GWASs) for stroke in adults, such studies for stroke of pediatric onset are lacking. Here we report the results of the first GWAS on pediatric stroke using a large cohort of 270 family-based trios. GWAS was performed using the Illumina 370 CNV single nucleotide polymorphisms array and analyzed using the transmission disequilibrium test as implemented in PLINK. An enrichment analysis was performed to identify additional true association signals among lower P value signals and searched for cumulatively associated genes within protein interaction data using dmGWAS. We observed clustering of association signals in 4 genes belonging to one family of metalloproteinases at high (ADAMTS12, P = 2.9 × 10−6; ADAMTS2, P = 8.0 × 10−6) and moderate (ADAMTS13, P = 9.3 × 10−4; ADAMTS17, P = 8.5 × 10−4) significance levels. Over-representation and gene-network analyses highlight the importance of the extracellular matrix in conjunction with members of the phosphoinositide and calcium signaling pathways in the susceptibility for pediatric stroke. Associated extracellular matrix components, such as ADAMTS proteins, in combination with misbalanced coagulation signals as unveiled by gene network analysis suggest a major role of postnatal vascular injury with subsequent thrombus formation as the leading cause of pediatric stroke.

Abstract 3336 Background: Genome wide association studies (GWAS) are the current method of choice to dissect the genetic basis of common complex diseases. Up-to-date, studies in families with a known first onset of symptomatic arterial or venous thrombosis (VT) in early childhood are lacking. Methods: Here, we performed a GWAS in a large family-based study sample comprising 241 nuclear families with pediatric VT using the Illumina 660W Infinium SNP array. The average genotype call rate was >99.5%, and the genomic inflation factor was a= 1.012. Single point and haplotype association was assessed using the Transmission Disequilibrium Test (TDT) as implemented in PLINK and FBAT, respectively, and corrected for multiple testing using permutation testing. In addition, associations were corrected for age, gender, and in a subsequent analysis for Factor VLeiden. Results and Conclusion: Four SNPs exceeded the threshold for genome wide significance in this dataset as determined by permutation testing using 100.000 bootstrap permutations (p Disclosures: No relevant conflicts of interest to declare.