来自多个队列的遗传分析意味着2200个可毒基因，端粒长度和白血病之间的因果关系

临床治疗性白血病的临床治疗靶点仍有待鉴定，白血病和端粒长度之间的因果关系尚不清楚。这项工作用CIS表达定量性状基因座（EQTL）的2,200个可吸毒基因用于来自EQTLGEN的eqTGEN群体和基因组范围的研究（GWAS）的七个telob sumber typer telom inter telob inter telob inter telob inter telob inter telom typer in telob and telob inter telm and telob inter nuk nuk in flow telob inter telm and telob inter tel telm and telm inten n y telob inter。暴露。 Finngen和Lee Lab的淋巴性白血病（LL）和髓样白血病（ML）的GWAS数据分别用作发现和复制队列的结果。从七个MR模型和一系列灵敏度分析产生了强大的Mendelian随机化（MR）发现。进一步实施了基于摘要数据的MR（SMR）分析和全转录组关联研究（TWA），以验证已鉴定的可药物基因与白血病之间的关联。单细胞类型的表达分析用于确定白血病休闲基因在人骨髓和外周血免疫细胞上的特定表达。进行了多变量MR分析，连锁不平衡评分回归（LDSC）和贝叶斯共定位分析，以进一步验证端粒长度与白血病之间的关系。调解分析用于评估通过端粒长度影响白血病的鉴定可药物基因的影响。 Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes.Combining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes （LY75，ADA，ABCA2）作为白血病的有前途的药物靶标。单变量MR分析表明，遗传预测的较高的白细胞端粒长度增加了LL的风险（优势比[OR] = 2.33，95％置信区间[95％CI] 1.70-3.18; P = 1.33E-07），并且没有异质性和水平的PLEONTAL PLEONTAL PLEOMTAL。来自两个队列的荟萃分析的证据加强了这一发现（OR = 1.88，95％CI 1.06-3.05; p = 0.01）。多变量MR分析表明，白细胞端粒长度与LL之间的因果关系，而没有其他六个血细胞端粒长度的干扰（OR = 2.72，95％CI 1.88-3.93; p = 1.23E-07）。 LDSC的证据支持白细胞端粒长度和LL之间的阳性遗传相关性（RG = 0.309，P = 0.0001）。共定位分析表明，LL上白细胞端粒长度的因果关系是由TERT区域的遗传变异rs770526驱动的。通过两步MR进行的调解分析表明，TYMP对LL的因果作用部分是由白细胞端粒长度介导的，介导的比例为12％。我们还发现，遗传学预测的较高的白细胞端粒长度增加了LL风险及其潜在的作用机理。

Clinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear.This work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes.Combining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70-3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06-3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88-3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %.Our study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.