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

Abstract

ABSTRACTBackgroundIschemic 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.MethodsWithin 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.ResultsFourteen 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.ConclusionsThis 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.