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We performed a genome-wide association study (GWAS) in a combined set of 800 childhood cases and 3865 controls in East Africa, controlling for age, sex, country, population-specific principal components, and a genetic relationship matrix. This analysis identified a BL-protective region within chromosome 21q22.12 tagged by the rs111457485-T allele (odds ratio [OR]\u2009=\u20090.57; <jats:italic>p<\/jats:italic>\u2009=\u20095.7\u2009\u00d7\u200910<jats:sup>\u22129<\/jats:sup>). The results were robust in standard meta-analysis (OR\u2009=\u20090.57, <jats:italic>p<\/jats:italic>\u2009&lt;\u20091.6\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>), sensitivity analyses (removing genomic outliers and related individuals), and after adjustment for Epstein-Barr virus (EBV) status. Genomic analyses revealed long-range (over ~700\u2009kb) chromatin interactions between the chr21q22.12 locus and the <jats:italic>RUNX1<\/jats:italic>-P1 promoter region. The African-specific rs2242780-C allele (<jats:italic>r<\/jats:italic>\n            <jats:sup>\n              <jats:italic>2<\/jats:italic>\n            <\/jats:sup>\u2009=\u20090.69 with the rs111457485-T allele in the study controls) showed increased enhancer activity in in-vitro Luciferase reporter assays (<jats:italic>p<\/jats:italic>\u2009=\u20094.5\u2009\u00d7\u200910<jats:sup>\u221210<\/jats:sup>), nominating it as the likely functional variant for the BL-associated loci. In addition to the association with reduced BL risk in GWAS (OR\u2009=\u20090.62, <jats:italic>p<\/jats:italic>\u2009=\u20092.24\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>), the rs2242780-C allele was also associated with better survival in patients with abdominal-only BL in exploratory analyses (hazard ratio\u2009=\u20090.39, <jats:italic>p<\/jats:italic>\u2009=\u20090.038, 106 patients, 59 deaths). Our GWAS uncovered novel BL-protective loci near <jats:italic>RUNX1<\/jats:italic>, offering insights into the genetic etiology of BL in African children.<\/jats:p>","DOI":"10.1038\/s41375-025-02690-8","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T07:46:19Z","timestamp":1752219979000},"page":"2196-2206","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A genome-wide association study identifies an African-specific locus on chromosome 21q22.12 associated with Burkitt lymphoma risk and survival"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6634-9040","authenticated-orcid":false,"given":"Diptavo","family":"Dutta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6711-5265","authenticated-orcid":false,"given":"Mateus 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