Department of Computational Biology, UNIL, Lausanne, 1015, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland.
Genome Biol. 2024 May 17;25(1):125. doi: 10.1186/s13059-024-03269-9.
Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry.
Using linear regression and bidirectional univariable and multivariable Mendelian randomization (MR), we elucidate the relationships between leukocyte telomere length (LTL) and 142 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, with these factors contributing to the majority of the 5.4% of LTL variance explained by the phenome. MR reveals 23 traits modulating LTL. Smoking cessation and high educational attainment associate with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associate with shorter LTL. We also identify 24 traits affected by LTL, with risk for cardiovascular, pulmonary, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through multivariable MR, we show that LTL may partially mediate the impact of educational attainment, body mass index, and female age at childbirth on proxied lifespan.
Our study sheds light on the modulators, consequences, and the mediatory role of telomeres, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.
端粒是染色体末端重复的 DNA 序列，随着细胞分裂而缩短。然而，调节端粒损耗及其健康后果的因素尚未完全了解。为了解决这个问题，我们利用了来自 326363 名无亲缘关系的欧洲血统的英国生物库参与者的数据。
使用线性回归和双向单变量和多变量孟德尔随机化（MR），我们阐明了白细胞端粒长度（LTL）与 142 种复杂特征之间的关系，包括疾病、生物标志物和生活方式因素。我们证实端粒随年龄缩短，并显示男性的下降幅度大于女性，这些因素导致 LTL 可解释的表型的 5.4%的大部分。MR 揭示了 23 种调节 LTL 的特征。戒烟和高教育程度与 LTL 延长有关，而每周饮酒量、体重指数、尿酸水平以及女性生殖事件，如分娩，与 LTL 缩短有关。我们还确定了 24 种受 LTL 影响的特征，短的 LTL 会增加心血管、肺部和一些自身免疫性疾病的风险，而长的 LTL 会增加其他自身免疫性疾病和癌症的风险。通过多变量 MR，我们表明 LTL 可能部分介导教育程度、体重指数和女性分娩年龄对代际寿命的影响。
我们的研究揭示了端粒的调节剂、后果和中介作用，描绘了 LTL、疾病、生活方式和社会经济因素之间复杂的关系。
