Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood-cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of childhood ALL (2,666 affected individuals, 60,272 control individuals) and a multi-trait GWAS of nine blood-cell indices in the UK Biobank. We identified 3,000 blood-cell-trait-associated (p < 5.0 × 10⁻⁸) variants, explaining 4.0% to 23.9% of trait variation and including 115 loci associated with blood-cell ratios (LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio). ALL susceptibility was genetically correlated with lymphocyte counts (r_g = 0.088, p = 4.0 × 10⁻⁴) and PLR (r_g = −0.072, p = 0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (odds ratio [OR] = 1.16, p = 0.031) and strengthened after accounting for other cell types (OR = 1.43, p = 8.8 × 10⁻⁴). We observed positive associations with increasing LMR (OR = 1.22, p = 0.0017) and inverse effects for NLR (OR = 0.67, p = 3.1 × 10⁻⁴) and PLR (OR = 0.80, p = 0.002). Our study shows that a genetically induced shift toward higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.

急性淋巴细胞白血病（ALL）是最常见的儿童癌症。尽管 ALL 的遗传风险位点与血液学特征之间存在重叠，但血细胞稳态失调的病因学相关性仍不清楚。我们在一项针对儿童 ALL（2,666 名受影响个体，60,272 名对照个体）的全基因组关联研究 (GWAS) 和英国生物库中九种血细胞指数的多性状 GWAS 中调查了这个问题。我们鉴定了 3,000 个与血细胞性状相关 (p < 5.0 × 10 ^-8 ) 的变异，解释了 4.0% 至 23.9% 的性状变异，并包括 115 个与血细胞比率相关的位点（LMR，淋巴细胞与单核细胞比率； NLR，中性粒细胞与淋巴细胞的比率；PLR，血小板与淋巴细胞的比率。ALL易感性与淋巴细胞计数（r _g = 0.088，p = 4.0 × 10 ^-4）和PLR（r _g = -0.072，p = 0.0017）具有遗传相关性。在孟德尔随机化分析中，基因预测的淋巴细胞计数增加与 ALL 风险增加相关（比值比 [OR] = 1.16，p = 0.031），并在考虑其他细胞类型后得到加强（OR = 1.43，p = 8.8 × 10 ^−4））。我们观察到 LMR 增加（OR = 1.22，p = 0.0017）呈正相关，而 NLR（OR = 0.67，p = 3.1 × 10 ⁻⁴）和 PLR（OR = 0.80，p = 0.002）呈负相关。我们的研究表明，遗传诱导的总体淋巴细胞计数以及与单核细胞、中性粒细胞和血小板相关的较高淋巴细胞计数的转变，导致儿童 ALL 的易感性增加。