Genome Medicine (Feb 2024)
Novel functional insights into ischemic stroke biology provided by the first genome-wide association study of stroke in indigenous Africans
- Rufus O. Akinyemi,
- Hemant K. Tiwari,
- Vinodh Srinivasasainagendra,
- Onoja Akpa,
- Fred S. Sarfo,
- Albert Akpalu,
- Kolawole Wahab,
- Reginald Obiako,
- Morenikeji Komolafe,
- Lukman Owolabi,
- Godwin O. Osaigbovo,
- Olga A. Mamaeva,
- Brian A. Halloran,
- Joshua Akinyemi,
- Daniel Lackland,
- Olugbo Y. Obiabo,
- Taofik Sunmonu,
- Innocent I. Chukwuonye,
- Oyedunni Arulogun,
- Carolyn Jenkins,
- Abiodun Adeoye,
- Atinuke Agunloye,
- Okechukwu S. Ogah,
- Godwin Ogbole,
- Adekunle Fakunle,
- Ezinne Uvere,
- Motunrayo M. Coker,
- Akinkunmi Okekunle,
- Osahon Asowata,
- Samuel Diala,
- Mayowa Ogunronbi,
- Osi Adeleye,
- Ruth Laryea,
- Raelle Tagge,
- Sunday Adeniyi,
- Nathaniel Adusei,
- Wisdom Oguike,
- Paul Olowoyo,
- Olayinka Adebajo,
- Abimbola Olalere,
- Olayinka Oladele,
- Joseph Yaria,
- Bimbo Fawale,
- Philip Ibinaye,
- Olalekan Oyinloye,
- Yaw Mensah,
- Omotola Oladimeji,
- Josephine Akpalu,
- Benedict Calys-Tagoe,
- Hamisu A. Dambatta,
- Adesola Ogunniyi,
- Rajesh Kalaria,
- Donna Arnett,
- Charles Rotimi,
- Bruce Ovbiagele,
- Mayowa O. Owolabi,
- for the SIREN Team
Affiliations
- Rufus O. Akinyemi
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan
- Hemant K. Tiwari
- Department of Biostatistics, University of Alabama at Birmingham
- Vinodh Srinivasasainagendra
- Department of Biostatistics, University of Alabama at Birmingham
- Onoja Akpa
- Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan
- Fred S. Sarfo
- Department of Medicine, Kwame Nkrumah University of Science and Technology
- Albert Akpalu
- Department of Medicine, University of Ghana Medical School
- Kolawole Wahab
- Department of Medicine, University of Ilorin Teaching Hospital
- Reginald Obiako
- Department of Medicine, Ahmadu Bello University
- Morenikeji Komolafe
- Department of Medicine, Obafemi Awolowo University Teaching Hospital
- Lukman Owolabi
- Department of Medicine, Aminu Kano Teaching Hospital
- Godwin O. Osaigbovo
- Jos University Teaching Hospital
- Olga A. Mamaeva
- Department of Epidemiology, School of Public Health University of Alabama at Birmingham
- Brian A. Halloran
- Department of Pediatrics, Volker Hall University of Alabama at Birmingham
- Joshua Akinyemi
- Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan
- Daniel Lackland
- Medical University of South Carolina
- Olugbo Y. Obiabo
- Delta State University/Delta State University Teaching Hospital
- Taofik Sunmonu
- Department of Medicine, Federal Medical Centre
- Innocent I. Chukwuonye
- Department of Medicine, Federal Medical Centre Umuahia
- Oyedunni Arulogun
- Department of Health Education, Faculty of Public Health, University of Ibadan
- Carolyn Jenkins
- Medical University of South Carolina
- Abiodun Adeoye
- Department of Medicine, College of Medicine, University of Ibadan
- Atinuke Agunloye
- Department of Medicine, College of Medicine, University of Ibadan
- Okechukwu S. Ogah
- Department of Medicine, College of Medicine, University of Ibadan
- Godwin Ogbole
- Department of Medicine, College of Medicine, University of Ibadan
- Adekunle Fakunle
- Department of Medicine, College of Medicine, University of Ibadan
- Ezinne Uvere
- Department of Medicine, College of Medicine, University of Ibadan
- Motunrayo M. Coker
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan
- Akinkunmi Okekunle
- Department of Food and Nutrition, Seoul National University
- Osahon Asowata
- Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan
- Samuel Diala
- Department of Medicine, College of Medicine, University of Ibadan
- Mayowa Ogunronbi
- Department of Medicine, Federal Medical Centre
- Osi Adeleye
- Department of Medicine, Federal Medical Centre
- Ruth Laryea
- Department of Medicine, University of Ghana Medical School
- Raelle Tagge
- Weill Institute for Neurosciences, School of Medicine, University of California San-Francisco
- Sunday Adeniyi
- Department of Medicine, University of Ilorin Teaching Hospital
- Nathaniel Adusei
- Department of Medicine, Kwame Nkrumah University of Science and Technology
- Wisdom Oguike
- Department of Medicine, Ahmadu Bello University
- Paul Olowoyo
- Federal Teaching Hospital
- Olayinka Adebajo
- Department of Medicine, College of Medicine, University of Ibadan
- Abimbola Olalere
- Department of Medicine, College of Medicine, University of Ibadan
- Olayinka Oladele
- Department of Medicine, College of Medicine, University of Ibadan
- Joseph Yaria
- Department of Medicine, College of Medicine, University of Ibadan
- Bimbo Fawale
- Department of Medicine, Obafemi Awolowo University Teaching Hospital
- Philip Ibinaye
- Department of Medicine, Ahmadu Bello University
- Olalekan Oyinloye
- Department of Medicine, Obafemi Awolowo University Teaching Hospital
- Yaw Mensah
- Department of Medicine, Kwame Nkrumah University of Science and Technology
- Omotola Oladimeji
- Department of Medicine, College of Medicine, University of Ibadan
- Josephine Akpalu
- Department of Medicine, University of Ghana Medical School
- Benedict Calys-Tagoe
- Department of Medicine, Kwame Nkrumah University of Science and Technology
- Hamisu A. Dambatta
- Department of Medicine, Aminu Kano Teaching Hospital
- Adesola Ogunniyi
- Department of Medicine, College of Medicine, University of Ibadan
- Rajesh Kalaria
- Translational and Clinical Research Institute, Newcastle University
- Donna Arnett
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina
- Charles Rotimi
- Center for Genomics and Global Health, National Human Genome Research Institute, NIH
- Bruce Ovbiagele
- Genetics and Cell Biology Unit, Department of Zoology, Faculty of Science, University of Ibadan
- Mayowa O. Owolabi
- Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan
- for the SIREN Team
- DOI
- https://doi.org/10.1186/s13073-023-01273-5
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 22
Abstract
Abstract 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.
Keywords
