title: A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke.
abstract: 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.
authors.affiliation: Leibniz-Institute for Arteriosclerosis Research at the University Muenster, Muenster, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Arning
authors.forename: Milan
authors.initials: M
authors.lastname: Hiersche
authors.forename: Anika
authors.initials: A
authors.lastname: Witten
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kurlemann
authors.forename: Karin
authors.initials: K
authors.lastname: Kurnik
authors.forename: Daniela
authors.initials: D
authors.lastname: Manner
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*; D049490:Systems Biology / Q000379:methods
chemical_list: D051722:ADAM Proteins