Genome‐wide association study of early ischaemic stroke risk in Brazilian individuals with sickle cell disease implicatesADAMTS2andCDK18and uncovers novel loci

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Abstract
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 (ADAMTS2(rs147625068,p = 3.70 × 10−9) andCDK18(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 geneTBC1D32(p = 3.36 × 10−10), rs188599171 nearCUX1(p = 5.89 × 10−11), rs77900855 nearBTG1(p = 4.66 × 10−8), and rs141674494 nearVPS13C(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.
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Funding Information
  • National Heart, Lung, and Blood Institute (HHSN2682011‐00001I, HHSN2682011‐00002I, HHSN2682011‐00003I, HHSN2682011‐00004I, HHSN2682011‐00005I, HHSN2682011‐00006I, HHSN2682011‐00007I, HHSN2682011‐00008I, HHSN2682011‐00009I, 75N2019D00033, R21 HL135367)
  • National Institutes of Health
  • National Cancer Institute
  • National Human Genome Research Institute
  • National Institute on Drug Abuse
  • National Institute of Mental Health
  • National Institute of Neurological Disorders and Stroke

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