Genome‐wide association study of early ischaemic stroke risk in Brazilian individuals with sickle cell disease implicates ADAMTS2 and CDK18 and uncovers novel loci. (5th January 2023) - Earley, Eric Jay
Summary: Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans‐Omics for Precision Medicine (TOPMed), a genome‐wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional‐hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome‐wide significance ( p < 5 × 10 −8 ) include two near genes 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 ). Meta‐analysis, which included the independent SCD cohorts Walk‐PHaSST and PUSH, exhibited consistent association for variants rs1209987 near gene TBC1D32 ( p = 3.36 × 10 −10 ), rs188599171 near CUX1 ( p = 5.89 × 10 −11 ), rs77900855 near BTG1 ( p = 4.66 × 10 −8 ), and rs141674494 near VPS13C (1.68 × 10 −9 ). Findings from this study support a multivariant model of early ischaemic stroke risk and possibly a shared genetic architecture between SCD individuals and non‐SCD individuals younger than 65 years.