多队列遗传分析暗示2200个药物靶向基因、端粒长度与白血病之间的因果关系

白血病的临床治疗靶点尚待确定，且白血病与端粒长度之间的因果关系尚不清楚。本研究利用了来自eQTLGen联盟的2,200个药物靶向基因的顺式表达数量性状位点（cis eQTL）以及英国生物库（UK Biobank）、荷兰队列中七种血细胞类型的端粒长度的全基因组关联研究（GWAS）总结数据，作为暴露指标。来自FinnGen和Lee实验室的淋巴细胞白血病（LL）和髓系白血病（ML）的GWAS数据被用作发现队列和验证队列的结果。通过七个MR模型和一系列敏感性分析，生成了稳健的孟德尔随机化（MR）结果。进一步利用基于总结数据的MR（SMR）分析和转录组全基因关联研究（TWAS）验证了所识别药物靶基因与白血病的关联。单细胞类型表达分析被用以识别白血病因果基因在人体骨髓和外周血免疫细胞中的特异性表达。多变量MR分析、连锁不平衡得分回归（LDSC）以及贝叶斯共定位分析被用以进一步验证端粒长度与白血病的关系。中介分析用于评估通过端粒长度影响白血病的药物靶向基因的作用。phenome-wide MR（Phe-MR）分析评估白血病因果基因和端粒长度对1,403种疾病表型的影响。结合两队列MR估算的Meta分析结果、SMR和TWAS分析，我们识别出五个LL的因果基因（TYMP、DSTYK、PPIF、GDF15、FAM20A）和三个ML的因果基因（LY75、ADA、ABCA2），作为有潜力的白血病药物靶点。单变量MR分析显示，遗传预测的较长白细胞端粒长度增加LL的风险（比值比[OR] = 2.33，95%置信区间[CI] 1.70-3.18；P = 1.33E-07），无异质性和水平多效性。两队列Meta分析的证据进一步加强了这一发现（OR = 1.88，95% CI 1.06-3.05；P = 0.01）。多变量MR分析显示，白细胞端粒长度与LL的因果关系不受其他六种血细胞端粒长度的干扰（OR = 2.72，95% CI 1.88-3.93；P = 1.23E-07）。LDSC分析支持白细胞端粒长度与LL之间的正遗传相关（rg = 0.309，P = 0.0001）。共定位分析显示，白细胞端粒长度对LL的因果作用由TERT区域的遗传变异rs770526驱动。通过两步MR的中介分析表明，TYMP对LL的因果作用部分通过白细胞端粒长度中介，中介比例为12%。本研究识别了几种与白血病风险相关的药物靶向基因，为白血病的病因学和药物开发提供了新见解。我们还发现，遗传预测的较长白细胞端粒长度会增加LL的风险，其潜在作用机制值得进一步研究。

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.