食道鳞状细胞癌（ESCC）在撒哈拉以南非洲地区具有较高的疾病负担，并且预后非常差。主要针对东亚人口的ESCC全基因组关联研究（GWAS）表明在其发病学中存在重要的遗传因素，但是还没有对非洲血统人口进行全基因组研究。在这里，我们报告了对1,686例患有ESCC的非洲个体和3,217例人群匹配对照个体进行GWAS，以研究其遗传发病学。我们在FAM120A启动子前（rs12379660，p = 4.58 × 10-8，比值比= 1.28，95％可信区间= 1.22-1.34）处发现了一个基因组范围内显著风险位点，并且在染色体2（rs142741123，p = 5.49 × 10-8）的MYO1B内发现了一个潜在的非洲特异性风险位点。FAM120A是氧化应激诱导生存信号的组成部分，在FAM120A位点的相关变异体与食道黏膜和食道肌层组织中的FAM120AOS中高度显著的cis-eQTL共定位。然后，在非洲ESCC研究和中国ESCC研究的组合中，通过种族跨群体的元分析共同鉴定了3,699名ESCC患者和5,918名对照个体上的三个基因组范围内显著位点，其中包括位于FAM120A上的染色体9（rs12379660，pmeta = 9.36 × 10-10），位于PLCE1上的染色体10（rs7099485，pmeta = 1.48 × 10-8）和位于CHEK2上的染色体22（rs1033667，pmeta = 1.47 × 10-9）。这表明ESCC在非洲和亚洲人群中存在共享和独特的遗传风险位点。我们在非洲血统人群中进行的ESCC GWAS表明在非洲ESCC风险的发病中有重要的遗传因素贡献。版权所有©2023美国人类遗传学学会。保留所有权利。

Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4.58 × 10-8, odds ratio = 1.28, 95% confidence interval = 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p = 5.49 × 10-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized with highly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, pmeta = 9.36 × 10-10), chromosome 10 at PLCE1 (rs7099485, pmeta = 1.48 × 10-8), and chromosome 22 at CHEK2 (rs1033667, pmeta = 1.47 × 10-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.Copyright © 2023 American Society of Human Genetics. All rights reserved.