Abstract 3336


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<10−5), and are likely true associations. Among these, 2 SNPs reside in a region on chromosome 6q13 comprising the gene for beta-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 (HNK1) carbohydrate pathway are associated with pediatric VT with p-values for rs1304029 (p=3.42×10−6) and rs2748331 (p=6.92×10−6). The corresponding haplotype association test resulted in a p=5.37×10−6 for the GA-haplotype, further underlining the robustness of the association. The SNPs rs636434 on chromosome 6q12 and rs1565242 on chromosome 15 both reside within hypothetical genes and are associated with VT with a p=2.70×10−6 and p=8.24×10−6, respectively. Additional SNPs exceeding a p<10−5 are included in subsequent analyses looking at gene networks and replication in independent study samples including our second GWAS on pediatric thromboembolic stroke (TS). Future studies using larger study samples are warranted to validate these findings and to characterize the genetic architecture underlying VT and TS in children.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.