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

作者：Rufus Akinyemi, Hemant K. Tiwari, Vinodh Srinivasasainagendra, Onoja Matthew Akpa, Fred Stephen Sarfo, Albert Kwaku Akpalu, Kolawole Wahab, Reginald Obiako, Morenikeji Adeyoyin Komolafe, Lukman Femi Owolabi, Godwin Osaigbovo, Olga A. Mamaeva, Brian Halloran, Joshua Odunayo Akinyemi, Daniel T. Lackland, Olugbo Y. Obiabo, Taofik O. Sunmonu, Innocent Ijezie Chukwuonye, Oyedunni Arulogun, Carolyn M. Jenkins, Abiodun Moshood Adeoye, Atinuke M. Agunloye, Okechukwu Samuel Ogah, Godwin Inalegwu Ogbole, Adekunle Gregory Fakunle, Ezinne Uvere, Motunrayo M. Coker, Akinkunmi Paul Okekunle, Osahon Jeffery Asowata, Samuel Diala, Mayowa Ogunronbi, Osi Adeleye, Ruth Y. Laryea, Raelle Tagge, Sunday Adeniyi, Nathaniel Adusei, Wisdom Oguike, Paul Olowoyo, Olayinka J. Adebajo, Abimbola Olalere, Olayinka Oladele, Joseph O. Yaria, Bimbo Fawale, Philip Ibinaye, Olalekan Ibukun Oyinloye, Yaw Mensah, Omotola Oladimeji, Josephine Akpalu, Benedict NL Calys-Tagoe, Hamisu A. Dambatta, Adesola O. Ogunniyi, Raj N. Kalaria, Donna K. Arnett, Charles N. Rotimi, Bruce Ovbiagele, Mayowa Ojo Owolabi, for the SIREN Team · 发表于：Genome Medicine · 年份：2024 · DOI：10.1186/s13073-023-01273-5 · 被引用次数：21 · 研究领域：Genetic Associations and Epidemiology、Acute Ischemic Stroke Management、Forensic and Genetic Research

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...