Background: Telomere length is an important indicator of tumor progression and survival for cancer patients. Previous work investigated the associations between genetically predicted telomere length and cancers; however, the types of cancers investigated in those studies were relatively limited or the telomere length-associated genetic variants employed often came from genome-wide association studies (GWASs) with small sample sizes. Methods: We constructed the genetic risk score (GRS) for leukocyte telomere length based on 17 associated genetic variants available from the largest telomere length GWAS up to 78,592 individuals. Then, a comprehensive analysis was undertaken to evaluate the association between the constructed GRS and the risk or mortality of a wide range of cancers [i.e., 37 cancers in the UK Biobank and 33 cancers in The Cancer Genome Atlas (TCGA)]. We further applied the two-sample Mendelian randomization (MR) to estimate the causal effect of leukocyte telomere length on UK Biobank cancers via summary statistics. Results: In the UK Biobank dataset, we found that the GRS of leukocyte telomere length was associated with a decreased risk of nine types of cancer (i.e., significant association with multiple myeloma, chronic lymphocytic leukemia, kidney/renal cell cancer, bladder cancer, malignant melanoma, basal cell carcinoma, and prostate cancer and suggestive association with sarcoma/fibrosarcoma and Hodgkin's lymphoma/Hodgkin's disease). In addition, we found that the GRS was suggestively associated with an increased risk of leukemia. In the TCGA dataset, we observed suggestive evidence that the GRS was associated with a high death hazard of rectum adenocarcinoma (READ), sarcoma (SARC), and skin cutaneous melanoma (SKCM), while the GRS was associated with a low death hazard of kidney renal papillary cell

BackgroundIn two-sample Mendelian randomization (MR) studies, sex instrumental heterogeneity is an important problem needed to address carefully, which however is often overlooked and may lead to misleading causal inference.MethodsWe first employed cross-trait linkage disequilibrium score regression (LDSC), Pearson’s correlation analysis, and the Cochran’s Q test to examine sex genetic similarity and heterogeneity in instrumental variables (IVs) of exposures. Simulation was further performed to explore the influence of sex instrumental heterogeneity on causal effect estimation in sex-specific two-sample MR analyses. Furthermore, we chose breast/prostate cancer as outcome and four anthropometric traits as exposures as an illustrative example to illustrate the importance of taking sex heterogeneity of instruments into account in MR studies.ResultsThe simulation definitively demonstrated that sex-combined IVs can lead to biased causal effect estimates in sex-specific two-sample MR studies. In our real applications, both LDSC and Pearson’s correlation analyses showed high genetic correlation between sex-combined and sex-specific IVs of the four anthropometric traits, while nearly all the correlation coefficients were larger than zero but less than one. The Cochran’s Q test also displayed sex heterogeneity for some instruments. When applying sex-specific instruments, significant discrepancies in the magnitude of estimated causal effects were detected for body mass index (BMI) on breast cancer (P = 1.63E-6), for hip circumference (HIP) on breast cancer (P = 1.25E-20), and for waist circumference (WC) on prostate cancer (P = 0.007) compared with those generated with sex-combined instruments.ConclusionOur study reveals that the sex instrumental heterogeneity has non-ignorable impact on sex-specific two-sample MR studies and the causal effects of anthropometric traits on breast/prostate cancer would be biased if sex-combined IVs are incorrectly employed.

BackgroundMultiple genes were previously identified to be associated with cervical cancer; however, the genetic architecture of cervical cancer remains unknown and many potential causal genes are yet to be discovered.MethodsTo explore potential causal genes related to cervical cancer, a two-stage causal inference approach was proposed within the framework of Mendelian randomization, where the gene expression was treated as exposure, with methylations located within the promoter regions of genes serving as instrumental variables. Five prediction models were first utilized to characterize the relationship between the expression and methylations for each gene; then, the methylation-regulated gene expression (MReX) was obtained and the association was evaluated via Cox mixed-effect model based on MReX. We further implemented the aggregated Cauchy association test (ACAT) combination to take advantage of respective strengths of these prediction models while accounting for dependency among the p-values.ResultsA total of 14 potential causal genes were discovered to be associated with the survival risk of cervical cancer in TCGA when the five prediction models were separately employed. The total number of potential causal genes was brought to 23 when conducting ACAT. Some of the newly discovered genes may be novel (e.g., YJEFN3, SPATA5L1, IMMP1L, C5orf55, PPIP5K2, ZNF330, CRYZL1, PPM1A, ESCO2, ZNF605, ZNF225, ZNF266, FICD, and OSTC). Functional analyses showed that these genes were enriched in tumor-associated pathways. Additionally, four genes (i.e., COL6A1, SYDE1, ESCO2, and GIPC1) were differentially expressed between tumor and normal tissues.ConclusionOur study discovered promising candidate genes that were causally associated with the survival risk of cervical cancer and thus provided new insights into the genetic etiology of cervical cancer.

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genomewide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population. Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal multisystem neurodegenerative disease, leading to substantial public health threat although it is relatively rare worldwide. However, the cause and pathogenesis underlying ALS mostly remains unknown, with few replicable and definitive risk factors and scarce drugs available 1-4. The number of ALS cases is predicted to increase dramatically due to population aging in the coming years 5 , which would further aggravate the ALS-associated social and economic burden. Therefore, the identification of its risk factors can provide better understanding of ALS and has the potential to pave the way for therapeutic intervention. In the past few years the role of telomere in various complex diseases has attracted much attention 6. Progressive telomere shortening occurs in all dividing normal cells due to incomplete synthesis of DNA lagging-strand, oxidative damage and other factors, which ultimately leads to cellular growth arrest or apoptosis that is thought to be an initial proliferative barrier to tumor development in humans 7. Indeed, recent studies suggested that leukocyte telomere length (LTL) was widely relevant to age-related diseases and disorders (e.g. many types of cancer and coronary heart disease) 8-11. In particular, it was demonstrated that shorter LTL was associated with various neurodegenerative disorders. For example, a latest study showed LTL at baseline and 18 months was shorter in patients of Parkinson's disease (PD) compared to healthy controls 12 , although prior studies found nonsignificant association between LTL and PD (Table 1). In addition, telomere shortening was recognized as an indicator of progression for Alzheimer's disease (AD) (Table 1). However, the knowledge about the relationship between LTL and ALS is very limited. Previous studies proposed th...

Clear cell renal cell carcinoma (ccRCC) is the main type of malignancy in kidney related to glucose metabolism. Primary single cell culture and single cell sequencing are novel research technologies. In this study, we explored the differentiation status of ccRCC cells and its significance in prognosis and immunotherapeutic response through bioinformatics. We characterized distinct differentiation states and differentiation-related genes (DRGs) in ccRCC cells through single cell RNA sequencing (scRNA-seq) analysis. Combined with bulk RNA-seq data, we classified patients into two clusters and found that this classification was closely correlated with patient prognosis and immunotherapeutic responses. Based on machine learning, we identified a prognostic risk model composed of 14 DRGs, including BTG2, CDKN1A, COL6A1, CPM, CYB5D2, FOSB, ID2, ISG15, PLCG2, SECISBP2, SOCS3, TES, ZBTB16, and ZNF704, to predict the survival rate of patients and then constructed a nomogram model integrating clinicopathological characteristics and risk score for clinical practice. In the study of immune checkpoints, we found that patients in the high-risk group had a disposition to get worse prognosis and better effects of immune checkpoint blocking therapies. Finally, we found the expression level of model DRGs was associated with a tumor-immune microenvironment (TIME) pattern and the response of 83 compounds or inhibitors was significantly different in the two risk groups. In a word, our study highlights the potential contribution of cell differentiation in prognosis judgment and immunotherapy response and offers promising therapeutic options for ccRCC patients.