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There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = − 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative. [ABSTRACT FROM AUTHOR]

Observational studies have suggested that the use of antihypertensive drugs was associated with the risk of frailty; however, these findings may be biased by confounding and reverse causality. This study aimed to explore the effect of genetically predicted lifelong lowering blood pressure (BP) through different antihypertensive medications on frailty. One‐sample Mendelian randomization (MR) and summary data‐based MR (SMR) were applied. We utilized two kinds of genetic instruments to proxy the antihypertensive medications, including genetic variants within or nearby drugs target genes associated with systolic/diastolic BP, and expression level of the corresponding gene. Among 298,618 UK Biobank participants, one‐sample MR analysis observed that genetically proxied BB use (relative risk ratios, 0.76; 95% CI, 0.65–0.90; p = 0.001) and CCB use (0.83; 0.72–0.95; p = 0.007), equivalent to a 10‐mm Hg reduction in systolic BP, was significantly associated with lower risk of pre‐frailty. In addition, although not statistically significant, the effect directions of systolic BP through ACEi variants (0.72; 0.39–1.33; p = 0.296) or thiazides variants (0.74; 0.53–1.03; p = 0.072) on pre‐frailty were also protective. Similar results were obtained in analyses for diastolic BP. SMR of expression in artery showed that decreased expression level of KCNH2, a target gene of BBs, was associated with lower frailty index (beta −0.02, p = 2.87 × 10−4). This MR analysis found evidence that the use of BBs and CCBs was potentially associated with reduced frailty risk in the general population, and identified KCNH2 as a promising target for further clinical trials to prevent manifestations of frailty. [ABSTRACT FROM AUTHOR]

The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors—such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin—higher alcohol drinking, and lower education attainment with increased EOCRC risk. Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions. • We conducted GWAS and MR analyses to identify the causes of EOCRC. • We identified two novel risk loci specific to EOCRC and confirmed the involvement of several known CRC risk variants in EOCRC. • We also identified new EOCRC risk genes and highlighted the prominent role of pathways such as insulin signaling in EOCRC. • We identified probable causal associations for body size, fasting insulin, alcohol intake, and educational level with EOCRC. [ABSTRACT FROM AUTHOR]

Background: Previous research has emphasized the potential benefits of anti-diabetic medications in inhibiting the exacerbation of Chronic Obstructive Pulmonary Disease (COPD), yet the role of anti-diabetic drugs on COPD risk remains uncertain. Methods: This study employed a Mendelian randomization (MR) approach to evaluate the causal association of genetic variations related to six classes of anti-diabetic drug targets with COPD. The primary outcome for COPD was obtained from the Global Biobank Meta-analysis Initiative (GBMI) consortium, encompassing a meta-analysis of 12 cohorts with 81,568 cases and 1,310,798 controls. Summary-level data for HbA1c was derived from the UK Biobank, involving 344,182 individuals. Positive control analysis was conducted for Type 2 Diabetes Mellitus (T2DM) to validate the choice of instrumental variables. The study applied Summary-data-based MR (SMR) and two-sample MR for effect estimation and further adopted colocalization analysis to verify evidence of genetic variations. Results: SMR analysis revealed that elevated KCNJ11 gene expression levels in blood correlated with reduced COPD risk (OR = 0.87, 95% CI = 0.79–0.95; p = 0.002), whereas an increase in DPP4 expression corresponded with an increased COPD incidence (OR = 1.18, 95% CI = 1.03–1.35; p = 0.022). Additionally, the primary method within MR analysis demonstrated a positive correlation between PPARG-mediated HbA1c and both FEV1 (OR = 1.07, 95% CI = 1.02–1.13; P = 0.013) and FEV1/FVC (OR = 1.08, 95% CI = 1.01–1.14; P = 0.007), and a negative association between SLC5A2-mediated HbA1c and FEV1/FVC (OR = 0.86, 95% CI = 0.74–1.00; P = 0.045). No colocalization evidence with outcome phenotypes was detected (all PP.H4 < 0.7). Conclusion: This study provides suggestive evidence for anti-diabetic medications' role in improving COPD and lung function. Further updated MR analyses are warranted in the future, following the acquisition of more extensive and comprehensive data, to validate our results. [ABSTRACT FROM AUTHOR]

Background: In this study we used Mendelian randomization (MR) to investigate the potential causal association of lipoprotein (a) [Lp(a)] levels with pulse wave velocity (PWV). Methods: Genetic variants associated with Lp(a) were retrieved from the UK Biobank GWAS (N = 290,497). A non‐ overlapping GWAS based on a European cohort (N = 7,000) was used to obtain genetic associations with PWV (outcome) and utilized two different measures for the same trait, brachial–ankle (baPWV) and carotid–femoral (cfPWV) PWV. We applied a two‐sample MR using the inverse variance weighting method (IVW) and a series of sensitivity analyses for 170 SNPs that were selected as instrumental variables (IVs). Results: Our analyses do not support a causal association between Lp(a) and PWV for neither measurement [βiwv(baPWV) = −.0005, p =.8 and βiwv(cfPWV) = −.006, p =.16]. The above findings were consistent across sensitivity analyses including weighted median, mode‐based estimation, MR‐Egger regression and MR‐PRESSO. Conclusion: We did not find evidence indicating that Lp(a) is causally associated with PWV, the gold standard marker of arterial stiffness. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether age at first sexual intercourse could lead to any changes in the risk of oral cavity cancer. Methods: A two-sample mendelian randomization was conducted using genetic variants associated with age at first sexual intercourse in UK biobank as instrumental variables. Summary data of Northern American from a previous genome-wide association study aimed at oral cavity cancer was served as outcome. Three analytical methods: inverse variance-weighted, mendelian randomization Egger, and weighted median were used to perform the analysis, among which inverse variance-weighted was set as the primary method. Robustness of the results was assessed through Cochran Q test, mendelian randomization Egger intercept tests, MR PRESSO, leave one out analysis and funnel plot. Results: The primary analysis provided substantial evidence of a positive causal relationship age at first sexual intercourse and the risk of oral cavity cancer (p = 0.0002), while a delayed age at first sexual intercourse would lead to a decreased risk of suffering oral cavity cancer (β = -1.013). The secondary outcomes confirmed the results (all β < 0) and all assessments supported the robustness, too (all p > 0.05). Conclusion: The study demonstrates that a delayed sexual debut would provide protection against OCC, thus education on delaying sexual intercourse should be recommended. [ABSTRACT FROM AUTHOR]

Background: The association between major depressive disorder (MDD) and irritable bowel syndrome (IBS) has been found in observational research; however, the causative relationship between MDD and IBS remains uncertain. Using the two‐sample Mendelian randomization (MR) approach, we attempted to examine the causal effect of MDD on IBS. Methods: Independent genetic variants for MDD identified by Howard et al. based on a genome‐wide meta‐analysis were selected for this study. Gene‐Outcome associations for IBS were gathered from UK Biobank and FinnGen databases. The MR analysis included inverse variance weighted (IVW), MR‐Egger regression, weighted median, weighted mode, and MR‐PRESSO sensitivity analyses. Results: FinnGen database subjected to inverse variance weighted (IVW) analysis revealed that MDD may be a risk factor for the development of IBS (OR = 1.356, 95% CI: 1.125–1.632, p = 0.0013). The same finding was reached in UK Biobank for IVW (OR = 1.011, 95% CI: 1.006–1.015, p = 3.18 × 10−7), MR‐Egger progression (OR = 1.030, 95% CI: 1.008–1.051, p = 0.007), and weighted median (OR = 1.011, 95% CI: 1.005–1.016, p = 0.0001). Conclusion: Our findings supported a causal relationship between MDD and IBS, which may have implications for the clinical management of IBS in individuals with MDD. [ABSTRACT FROM AUTHOR]

Background: Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development. Methods: Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID: ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings. Results: After Bonferron correction (p < 0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length. GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4 > 0.8). Conclusion: Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed. [ABSTRACT FROM AUTHOR]

Mechanisms through which most known Alzheimer's disease (AD) loci operate to increase AD risk remain unclear. Although Apolipoprotein E (APOE) is known to regulate lipid homeostasis, the effects of broader AD genetic liability on non-lipid metabolites remain unknown, and the earliest ages at which metabolic perturbations occur and how these change over time are yet to be elucidated. We examined the effects of AD genetic liability on the plasma metabolome across the life course. Using a reverse Mendelian randomization framework in two population-based cohorts [Avon Longitudinal Study of Parents and Children (ALSPAC, n = 5648) and UK Biobank (n ≤ 118,466)], we estimated the effects of genetic liability to AD on 229 plasma metabolites, at seven different life stages, spanning 8 to 73 years. We also compared the specific effects of APOE ε4 and APOE ε2 carriage on metabolites. In ALSPAC, AD genetic liability demonstrated the strongest positive associations with cholesterol-related traits, with similar magnitudes of association observed across all age groups including in childhood. In UK Biobank, the effect of AD liability on several lipid traits decreased with age. Fatty acid metabolites demonstrated positive associations with AD liability in both cohorts, though with smaller magnitudes than lipid traits. Sensitivity analyses indicated that observed effects are largely driven by the strongest AD instrument, APOE, with many contrasting effects observed on lipids and fatty acids for both ε4 and ε2 carriage. Our findings indicate pronounced effects of the ε4 and ε2 genetic variants on both pro- and anti-atherogenic lipid traits and sphingomyelins, which begin in childhood and either persist into later life or appear to change dynamically. [ABSTRACT FROM AUTHOR]

Genetic relationships between blood eosinophil count (BEC), asthma susceptibility, and severity are unclear. We sought to identify the genetic difference between type 2 (T2) and nontype 2 (non-T2) asthma (defined by BEC) and investigate genetic relationships between high BEC, asthma susceptibility, and severity. Genome-wide association studies (GWASs) were performed for T2 (n = 9,064; BEC ≥ 300 cells/μL) versus non-T2 asthma (n = 14,379; BEC < 150 cells/μL) and asthma susceptibility (37,227 asthmatics vs. 124,132 nonasthma controls) in the UK Biobank and asthma severity (moderate-to-severe asthma [n = 2,153] vs. mild asthma [n = 5165]) in the All of Us Research Program (AoURP). Genetic causality between BEC, asthma susceptibility, and severity were dissected using Mendelian randomization (MR). High BEC was associated with asthma and decreased pulmonary function. GWASs revealed four sets of genetic variants (p < 5 × 10−8): genes associated with only BEC or asthma and genes associated with high BEC and asthma in the same or opposite direction. The C allele of rs653178 in ATXN2 was associated with high BEC, risk for autoimmune diseases, and protection for asthma. Genetic variants associated with BEC or asthma were not associated with asthma severity. MR indicated high BEC and asthma were in bidirectional causal relationship (p <.001); however, they were not causal for asthma severity. Genetic variants associated with asthma or BEC and asthma severity are distinctive. High BEC is a risk factor for asthma; however, it is neither necessary nor sufficient for asthma susceptibility and severity. [ABSTRACT FROM AUTHOR]

The use of lipid-lowering drugs is still highly controversial in patients with amyotrophic lateral sclerosis (ALS). We performed a drug-target Mendelian randomization (MR) analysis to investigate the effect of targeted lipid-lowering drugs on the risk of ALS. First, we evaluated the causal relationship between HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase (HMGCR) inhibitors-taking trait and ALS using a bidirectional two-sample MR study. Second, we investigated the causal relationship between lipid-lowering drugs and ALS through a drug-target MR approach. The summary data for HMGCR inhibitors-taking traits were extracted from a genome-wide association study (GWAS) of medication use and associated disease in the UK Biobank. The summary data for low-density lipoprotein cholesterol and apolipoprotein B (apoB) were extracted from a meta-analysis of GWAS in individuals of European ancestry in the UKB. The GWAS summary data of ALS were obtained from the Project MinE. Our bidirectional two-sample MR showed that genetically determined increased HMGCR inhibitors-taking trait was an independent risk factor for ALS (odds ratio [OR] = 1.090, 95% confidence interval [CI] = 1.035–1.150, p = 0.001). The results of drug-target MR showed that the increased expression of the HMGCR gene in blood with the higher risk of ALS (OR = 1.21, 95% CI = 1.01–1.46; p = 0.042) through SMR method and the apoB level mediated by the APOB gene increased the risk of ALS (OR = 1.15; 95% CI =1.05–1.25; p = 0.001) through inverse-variance weighted MR method. This present study provides genetic support for a positive causal effect of HMGCR inhibitors-taking trait and ALS. The reason for this may be due to the underlying disease condition behind the medication, rather than the medication itself. Our findings also suggested that HMGCR and apoB inhibitors may have potential protective effects on ALS. [ABSTRACT FROM AUTHOR]

Background: Observational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. Methods: We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant's effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects. Results: The estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. Conclusions: Our findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified. [ABSTRACT FROM AUTHOR]

Background: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. Aims: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. Methods: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. Results: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). Conclusion: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. Data access statement: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables. [ABSTRACT FROM AUTHOR]