Examining the potential causal relationships among smoking, blood DNA methylation, and type 2 diabetes development: A Mendelian randomization study

Multi-population GWAS meta-analysis identifies bladder cancer susceptibility loci and highlights genetic regulation of smoking-related risk

Bladder cancer is the ninth most common cancer worldwide, caused by genetic and environmental risk factors. Here, we report the findings of a multi-population meta-analysis of genome-wide association studies, including 32,470 individuals with and 1,753,462 without bladder cancer. We identify 70 independent risk loci, of which 43 are novel. Using a 70-marker polygenic risk score (HR = 1.63 per standard deviation), we increase the area under the curve from 0.71 (baseline risk model) to 0.75. Integrative analyses reveal the enrichment of the associated variants within accessible chromatin regions, and of the prioritized genes within pathways for xenobiotic metabolism and smoking behavior. Specifically, we show that the 15q25.1 variant rs71581744-ACCCC/A co-localizes with tissue-specific CHRNA3 expression, modulates mRNA stability, and associates with risk of muscle-invasive bladder cancer among current smokers. Together, these findings substantially expand the known genetic architecture of bladder cancer risk and highlight the germline regulation of smoking behavior as a mechanism driving bladder cancer susceptibility. This study integrates genetic data from diverse populations to identify 70 loci linked to bladder cancer risk, including 43 novel, and uses experimental approaches to uncover how inherited variation influences this risk in the context of smoking.

Evidence from European ancestry genome-wide association studies and a case-control study suggests several selenoproteins are linked to a decreased risk of Alzheimer's disease.

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder resulting from a complex interplay of multiple factors. Recent hypotheses suggest a potential role of selenium and selenoproteins in AD pathogenesis. However, the causality relationship between them remains to be elucidated.ObjectiveThis study investigates the causal link between selenoproteins and AD risk.MethodsWe analyzed the data by leveraging genome-wide association studies from European cohorts (90,338 AD patients and 1,036,225 controls) and expression quantitative trait loci (eQTLs) from eQTLGen (31,684 individuals) and GTEx v8 (838 individuals). Mendelian randomization and summary data-based Mendelian randomization were applied to assess the potential causal associations between selenoproteins and AD. To further confirm these genetic associations at the clinical level, we conducted a case-control study to evaluate the levels of four differentially expressed selenoproteins in peripheral blood in individuals with AD and cognitively normal controls.ResultsOur analysis revealed that four selenoproteins, including selenoprotein S (SEPH2) and selenoprotein M (SELENOM), glutathione peroxidase 4 (GPX4) and thioredoxin reductase 2 (TXNRD2), were correlated with a decreased risk of AD. The levels of GPX4, SELENOM, and TXNRD2 were found to be significantly downregulated in AD patients compared to controls in the case-control validation study, supporting the change identified in our genetic analysis.ConclusionsThis study provides genetic and clinical evidence that specific selenoproteins are associated with a decreased risk of AD. The findings highlight the potential role of these proteins in AD pathophysiology and suggest their promise as biomarkers or therapeutic targets, warranting further investigation.

Suggestive genome-wide associations with inflammatory biomarkers in an admixed population, including a missense variant in the OR6K6 olfactory receptor gene associated with MCP-1

New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.

LPA genetic variation is associated with type 2 diabetes after adjustment for lipoprotein(a) concentration: results of the Aragon Workers’ health study

Epidemiological and Mendelian randomization studies have reported an inverse relationship between lipoprotein(a) [Lp(a)] concentration and type 2 diabetes (T2D), although findings have not been uniform across studies. We hypothesized that genetic variation at the LPA locus may contribute to T2D development beyond circulating Lp(a) concentration alone, and therefore aimed to investigate the association between common LPA variation and incident T2D. We analysed 5058 male participants from the Aragon Workers’ Health Study with approximately 15 years of follow-up. T2D was defined as the presence of antidiabetic treatment or HbA1c ≥ 6.5%. Common LPA single-nucleotide variants (SNVs) with a minor allele frequency ≥ 1% were selected. Several weighted LPA genetic scores were constructed, with the 15-SNV score defined as the primary LPA genetic score and alternative and more restricted scores evaluated in sensitivity analyses. Associations of single LPA variants and LPA genetic scores with incident T2D were assessed using multivariable logistic regression models adjusted for age, body mass index, ln-transformed Lp(a), and a T2D polygenic risk score. False discovery rate correction was applied to account for multiple testing. Robustness was assessed using leave-one-out analyses and Cox proportional hazards models. Among 4744 participants free of T2D at baseline, 578 (12.2%) developed incident T2D. Baseline Lp(a) concentrations were lower in participants who developed incident T2D than in those who remained free of T2D (12.6 [5.0–32.5] versus 17.0 [6.1–40.0] mg/dL; p  < 0.001). No individual LPA SNV remained significantly associated with incident T2D. In contrast, the primary 15-SNV LPA genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration (odds ratio per one-standard-deviation increase 1.17, 95% confidence interval 1.07–1.29; p  = 0.001). The 13-SNV, 12-SNV, 10-coding/splice, and 2-SNV raising-Lp(a) scores were also significantly associated with incident T2D after false discovery rate correction. The association with the 15-SNV LPA genetic score was supported by leave-one-out and Cox analyses. A 15-SNV LPA genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration and a T2D polygenic risk score. These findings suggest that common LPA variation represented by the 15-SNV genetic score may contribute to T2D risk through mechanisms not fully captured by circulating Lp(a) concentration alone.

Elucidating the proteomic pathways linking childhood body mass index with type 2 diabetes: a Mendelian randomization and recall-by-genotype study

The authors' study identified putative actionable proteins that could reduce the elevated T2D risk attributable to childhood adiposity in Europeans, but their relevance in Asian populations requires further investigation.

Association between antidepressant use and the risk of type 2 diabetes: a multi-stage Mendelian randomization study.