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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NHLBI TOPMed: REDS-III_Brazil (phs001468.v3.p1) was performed at Baylor (HHSN268201500015C, HHSN268201600033I) TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Molecular data and associated clinical and phenotype data are available within dbGaP