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Novel functional insights into ischemic stroke biology provided by the first genome-wide association study of stroke in indigenous Africans

Lookup NU author(s): Professor Raj KalariaORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2024. Background: African ancestry populations have the highest burden of stroke worldwide, yet the genetic basis of stroke in these populations is obscure. The Stroke Investigative Research and Educational Network (SIREN) is a multicenter study involving 16 sites in West Africa. We conducted the first-ever genome-wide association study (GWAS) of stroke in indigenous Africans. Methods: Cases were consecutively recruited consenting adults (aged > 18 years) with neuroimaging-confirmed ischemic stroke. Stroke-free controls were ascertained using a locally validated Questionnaire for Verifying Stroke-Free Status. DNA genotyping with the H3Africa array was performed, and following initial quality control, GWAS datasets were imputed into the NIH Trans-Omics for Precision Medicine (TOPMed) release2 from BioData Catalyst. Furthermore, we performed fine-mapping, trans-ethnic meta-analysis, and in silico functional characterization to identify likely causal variants with a functional interpretation. Results: We observed genome-wide significant (P-value < 5.0E−8) SNPs associations near AADACL2 and miRNA (MIR5186) genes in chromosome 3 after adjusting for hypertension, diabetes, dyslipidemia, and cardiac status in the base model as covariates. SNPs near the miRNA (MIR4458) gene in chromosome 5 were also associated with stroke (P-value < 1.0E−6). The putative genes near AADACL2, MIR5186, and MIR4458 genes were protective and novel. SNPs associations with stroke in chromosome 2 were more than 77 kb from the closest gene LINC01854 and SNPs in chromosome 7 were more than 116 kb to the closest gene LINC01446 (P-value < 1.0E−6). In addition, we observed SNPs in genes STXBP5-AS1 (chromosome 6), GALTN9 (chromosome 12), FANCA (chromosome 16), and DLGAP1 (chromosome 18) (P-value < 1.0E−6). Both genomic regions near genes AADACL2 and MIR4458 remained significant following fine mapping. Conclusions: Our findings identify potential roles of regulatory miRNA, intergenic non-coding DNA, and intronic non-coding RNA in the biology of ischemic stroke. These findings reveal new molecular targets that promise to help close the current gaps in accurate African ancestry-based genetic stroke’s risk prediction and development of new targeted interventions to prevent or treat stroke.


Publication metadata

Author(s): Akinyemi RO, Tiwari HK, Srinivasasainagendra V, Akpa O, Sarfo FS, Akpalu A, Wahab K, Obiako R, Komolafe M, Owolabi L, Osaigbovo GO, Mamaeva OA, Halloran BA, Akinyemi J, Lackland D, Obiabo OY, Sunmonu T, Chukwuonye II, Arulogun O, Jenkins C, Adeoye A, Agunloye A, Ogah OS, Ogbole G, Fakunle A, Uvere E, Coker MM, Okekunle A, Asowata O, Diala S, Ogunronbi M, Adeleye O, Laryea R, Tagge R, Adeniyi S, Adusei N, Oguike W, Olowoyo P, Adebajo O, Olalere A, Oladele O, Yaria J, Fawale B, Ibinaye P, Oyinloye O, Mensah Y, Oladimeji O, Akpalu J, Calys-Tagoe B, Dambatta HA, Ogunniyi A, Kalaria R, Arnett D, Rotimi C, Ovbiagele B, Owolabi MO

Publication type: Article

Publication status: Published

Journal: Genome Medicine

Year: 2024

Volume: 16

Online publication date: 05/02/2024

Acceptance date: 12/12/2023

Date deposited: 29/02/2024

ISSN (electronic): 1756-994X

Publisher: BioMed Central Ltd

URL: https://doi.org/10.1186/s13073-023-01273-5

DOI: 10.1186/s13073-023-01273-5

PubMed id: 38317187


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Funding

Funder referenceFunder name
1R01NS114045-01
1U01HG010273
1R13NS115395-01A1
3U24HG009780-03S5
African Neurobiobank for Precision Stroke Medicine: ELSI
CaNVAS
ARISES
D43TW012030
FCG/R1/201034
FLR/R1/191813
Growing Data-science Research in Africa to Stimulate Progress (GRASP)
H3Africa CVD Supplement
National Institutes of Health NIH/NINDS SIREN
R01NS107900-02S1
R01NS115944-01
Royal Society and the African Academy of Sciences
R01NS107900
UE5HL172183
SIBS Gen Gen
SIBS Genomics
Sub-Saharan Africa Conference on Stroke (SSACS)
Training Africans to Lead and Execute Neurological Trials & Studies (TALENTS)
U54HG007479

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