Genome-wide association study of ischemic stroke risk in Sickle Cell confirms ADAMTS2, CDK18, uncovers 12 novel loci

ABSTRACT Background Ischemic stroke is a common complication of sickle cell disease (SCD) and without screening or intervention can affect 11% of children with SCD before the age of 20. This study sought to find genetic biomarkers for risk of stroke occurring at younger ages. Methods Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischemic stroke was performed on 1,333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel proportional hazards analysis approach, we searched for variants associated with strokes occurring at younger ages. Results Fourteen genomic regions were associated with early ischemic stroke at genome wide significance (P<5×10 −8 ). This included variants near two genes which have been previously linked to non-SCD early onset stroke (<65 years): ADAMTS2 (rs147625068, P= 3.70 × 10 −9 ) and CDK18 (rs12144136, P= 2.38 × 10 −9 ), respectively. Individuals harboring multiple risk alleles exhibited increasing rates of stroke at earlier timepoints (P < 0.001, Gehan-Wilcoxon) than those carrying only one. Enrichment tests suggest systemic dysregulation of gene expression in the hypothalamus ( P = 0.03, FDR), substantia nigra ( P = 0.03), spleen ( P = 0.005) and coronary ( P = 0.0005), tibial ( P = 0.03) and aorta arteries ( P = 0.03. Conclusions This findings from this study support a model of shared genetic architecture underlying ischemic stroke risk between SCD individuals and non-SCD individuals <65 years. In addition, results suggest an additive liability due to carrying multiple risk alleles.