LBPO.PS01 · 人群科学 · Late-Breaking
全基因组关联研究鉴定出急性髓系白血病的种系易感位点
Genome-wide association study identifies germline susceptibility loci for acute myeloid leukemia
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：既往针对急性髓系白血病（AML）的全基因组关联研究（GWAS）受限于样本量和血统代表性。我们开展了迄今为止规模最大的多血统GWAS，以鉴定与AML相关的种系易感位点。
方法：本研究是NCI-CIBMTR®合作的血液与骨髓移植基因组研究（GS-BMT）项目的一部分。AML患者为异基因造血细胞移植（HCT）受者，在HCT前采集血样（82%处于完全形态学缓解状态）。无AML对照包括来自GS-BMT的HCT供者以及前列腺癌、肺癌、结直肠癌和卵巢癌（PLCO）筛查试验的参与者。样本在Illumina Global Screening Array平台上进行基因分型，向TOPMed v3参考面板进行填补，并使用REGENIE v4.1在加性模型下采用Firth近似似然比检验进行分析。模型对性别、年龄和遗传主成分进行了校正。对填补质量评分> 0.2且次要等位基因计数≥ 30的变异进行了检验。
结果：主要分析纳入10,937例病例和100,705例对照，涵盖多个遗传推断的血统群体，包括1,776例非欧洲血统病例。检验统计量膨胀有限（λ 1,000 = 1.001；LDSCR截距 = 1.014），表明残余混杂极小。我们观察到8个全基因组显著关联的基因组区域。其中，我们重点介绍5号染色体上的三个信号，包括位于5q35的rs141601766（OR = 22.79，95% CI = 14.34-36.20，P = 1.05×10-40），这是DDX41中一个罕见的非同义变异，在ClinVar中被归类为致病或可能致病，此前曾被认为与家族性AML易感相关；位于5q35的rs552806293（OR = 22.97，95% CI = 13.26-39.80，P = 1.03×10-28），这是UIMC1内的一个罕见内含子变异，该基因在DNA损伤应答中具有明确作用；以及位于5p15（TERT位点）的rs7705526（OR = 1.18，95% CI = 1.15-1.22，P = 6.65×10-25），这是一个常见变异，此前在大型GWAS中被发现与白细胞端粒长度、克隆性造血、骨髓增殖性肿瘤、血液学数量性状及卵巢浆液性癌相关。条件分析提示这两个5q35信号在统计上相互独立。
结论：本项多血统GWAS鉴定出多个与AML风险相关的种系易感位点。正在进行的工作包括血统特异性分析、分子分层分析和结局分析。
查看英文原文 English abstract
Background: Prior genome-wide association studies (GWAS) of acute myeloid leukemia (AML) have been limited by sample size and ancestry representation. We conducted the largest multi-ancestry GWAS to-date to identify germline susceptibility loci associated with AML.
Methods: The study is part of the NCI-CIBMTR® collaborative Genomic Studies in Blood and Marrow Transplantation (GS-BMT) project. Patients with AML were allogeneic hematopoietic cell transplantation (HCT) recipients with blood samples collected before HCT (82% were in complete morphologic remission). AML-free controls included HCT donors from GS-BMT and participants from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Samples were genotyped on Illumina Global Screening Array platforms, imputed to the TOPMed v3 reference panel, and analyzed using REGENIE v4.1 under an additive model with Firth-approximate likelihood ratio tests. Models were adjusted for sex, age, and genetic principal components. Variants with imputation quality score > 0.2 and minor allele count ≥ 30 were tested.
Results: The primary analysis included 10,937 cases and 100,705 controls spanning multiple genetically inferred ancestry groups, including 1,776 cases of non-European ancestry. Test statistic inflation was limited (λ 1,000 =1.001; LDSCR intercept=1.014), indicating minimal residual confounding. We observed eight genomic regions with genome-wide significant associations. Among these, we highlight three signals on chromosome 5, including rs141601766 at 5q35 (OR = 22.79, 95% CI = 14.34-36.20, P = 1.05×10 -40 ), a rare non-synonymous variant in DDX41 classified as pathogenic or likely pathogenic in ClinVar and previously implicated in familial AML predisposition; rs552806293 at 5q35 (OR = 22.97, 95% CI = 13.26-39.80, P = 1.03×10 -28 ), a rare intronic variant within UIMC1 , a gene with established roles in DNA damage response; and rs7705526 at 5p15 ( TERT locus; OR = 1.18, 95% CI = 1.15-1.22, P = 6.65×10 -25 ), a common variant previously associated with leukocyte telomere length, clonal hematopoiesis, myeloproliferative neoplasms, hematologic quantitative traits, and ovarian serous carcinoma in large GWAS. Conditional analyses suggested the two 5q35 signals were statistically independent.
Conclusions: This multi-ancestry GWAS identifies multiple germline susceptibility loci for AML risk. Ongoing work includes ancestry-specific, molecular-stratification, and outcome analyses.
利益披露 Disclosure
X. Wu, None..
F. Pirsl, None..
G. Schmidt, None..
M. Rafati, None..
A. Vogt, None..
H. Higson, None..
J. Liu, None..
J. Wang, None..
S. Gaddam, None..
S. Li, None..
W. Saber, None..
Y. Bolon, None..
S. Moore, None..
S. A. Savage, None..
S. Chanock, None..
S. Spellman, None..
P. Kraft, None..
S. M. Gadalla, None.