Independent Instruments Research Articles

Evaluating off-target drug effects seen in RCTs using proteomics and mendelian randomisation

Abstract Introduction Serious adverse drug effects are often not detected until late in drug development after thousands of patients have been exposed to an investigational drug in long and costly clinical trials. More efficient approaches are desirable. Proteomics-informed Mendelian randomisation (MR) can identify potential molecular mechanisms underlying off-target effects of pharmaceuticals and drug repurposing opportunities. Purpose As a demonstration of this approach, we used findings from a previous plasma proteomics study nested within a clinical trial of torcetrapib, which was terminated early because of an increased risk of cardiac events and mortality, in which 200 plasma proteins significantly increased (n=68) or decreased (n=132) after three months of torcetrapib use. We surveyed potential plasma protein-mediated causal effecs of torcetrapib on a wide array of relevant phenotypes in three broad domains: cardiovascular(n=10), immunological(n=9) and cancer(n=4), representing major categories of adverse outcomes that were more common in the treatment arm. Methods We performed three-sample MR on torcetrapib-associated proteins. First, we identified independent cis-pQTL instruments for these proteins in the Atherosclerosis Risk in Communities (ARIC) Study. Then, we used pQTL effect estimates from the deCODE study, to reduce the potential for bias due to winner’s curse and to increase precision. Lastly, we conducted MR analyses on disease-relevant phenotypes using a debiased-IVW estimator and summary results from the largest available GWAS on these phenotypes: coronary artery disease, ischaemic stroke, blood pressure, lipids, heart rate, QT interval, eGFR, serious infections, blood cell counts, immune cell fractions, and several cancers. The significance level for causal protein-phenotype associations was p=1.85E-5 (0.05/(104*26)), correcting for the 104 proteins with valid instruments and the 26 tested outcomes. Results Thirty-three proteins had evidence of a causal association with at least one phenotype. Seventeen proteins were associated with cardiovascular outcomes, including 8 for blood pressure and 9 for lipid levels. We identified more proteins, 25, associated with immune-related phenotypes. One protein was associated with cancer. Of note, 9 proteins had pleiotropic effects across several domains. Conclusions Our approach of using Mendelian randomisation to investigate the causal effects of plasma proteins impacted by medication with known off-target adverse effects revealed several novel causal relationships, highlighting the role of immune function in the development of cardiovascular disease. These results support the use of intermediate omics evaluation to identify potential biomarkers for safety monitoring for drug development and reveal avenues of investigation for drug repurposing.

Causal Relationship Between Autism Spectrum Disorder and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Patients with autism spectrum disorder (ASD) are often accompanied by inflammatory bowel disease (IBD) in observational research; however, the potential causal link between the two conditions remains unknown. In this study, we used a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal relationship between ASD and IBD and its main subtypes, Crohn's disease (CD), and ulcerative colitis (UC). Independent genetic instruments from a genome-wide association study (GWAS) for IBD (25,042 cases and 34,915 controls) were used to investigate the association of IBD with ASD data obtained from the PGC and the iPSYCH consortia (N = 46,351). The primary analysis employed the random effects inverse variance weighting (IVW) method. Horizontal pleiotropy was detected using the MR Egger regression and the MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis while heterogeneity was detected using Cochran's Q. The IVW method indicated a positive causal relationship of IBD with ASD (odds ratio (OR) = 1.028, 95% confidence interval (CI) = 1.001-1.056, p = 0.042). In subtype analyses, CD was positively related to ASD (OR = 1.036; 95% CI = 1.004-1.069; p = 0.02); however, UC showed no relationship (OR = 1.021; 95% CI = 0.999-1.044; p = 0.065). In contrast, no evidence of a causal relationship between ASD and IBD or its subtypes (p > 0.05) was found. Our findings provided evidence in support of potential causal associations between IBD/CD and ASD.

Impact of Assimilating Geostationary Interferometric Infrared Sounder Observations from Long- and Middle-Wave Bands on Weather Forecasts with a Locally Cloud-Resolving Global Model

The Geostationary Interferometric InfraRed Sounder (GIIRS) provides a novel opportunity to acquire high-spatiotemporal-resolution atmospheric information. Previous studies have demonstrated the positive impacts of assimilating GIIRS radiances from either long-wave temperature or middle-wave water vapor bands on modeling high-impact weather processes. However, the impact of assimilating both bands on forecast skill has been less investigated, primarily due to the non-identical geolocations for both bands. In this study, a locally cloud-resolving global model is utilized to assess the impact of assimilating GIIRS observations from both long-wave and middle-wave bands. The findings indicate that the GIIRS observations exhibit distinct inter-channel error correlations. Proper inflation of these errors can compensate for inaccuracies arising from the treatment of the geolocation of the two bands, leading to a significant enhancement in the usage of GIIRS observations from both bands. The assimilation of GIIRS observations not only markedly reduces the normalized departure standard deviations for most channels of independent instruments, but also improves the atmospheric states, especially for temperature forecasting, with a maximum reduction of 42% in the root-mean-square error in the lower troposphere. These improvements contribute to better performance in predicting heavy rainfall.

Causal association between hyperthyroidism and risk of gastroesophageal reflux or esophageal cancer: a bidirectional Mendelian randomization investigation.

Emerging observational studies indicated an association between hyperthyroidism and gastrointestinal disorders. However, it remains unclear whether this association is causal, particularly in the case of gastroesophageal reflux (GERD) and esophageal cancer. To assess the potential causal relationship between hyperthyroidism and GERD or esophageal cancer, we conducted a bidirectional 2-sample Mendelian randomization study. Independent genetic instruments for hyperthyroidism from the UK Biobank (N case=3,545 and N control=459,388) and public genome-wide association study (GWAS) dataset (N case=3,731 and N control=480,867) were used to investigate the association with esophageal cancer in the UK Biobank study (N case=740 and N control=372,016) and GERD in the public GWAS database (N case=20,381 and N control=464,217). Four different approaches (inverse variance weighted (IVW), weighted mode, MR-Egger, and weighted median regression) were used to ensure that our results more reliable. Additional sensitivity analyses were also performed to validate our results. When hyperthyroidism was considered as the exposure factor, it appeared to act as a protective factor for GERD (ORIVW = 0.88, 95% CI, 0.79-0.99, P = 0.039), while as a risk factor for esophageal cancer (ORIVW = 1.03, 95% CI, 1.01-1.06, P = 0.003). However, there is no evidence supporting a reverse causal relationship between genetic susceptibility to hyperthyroidism and GERD or esophageal cancer. Our findings provided genetic evidence supporting bidirectional causal relationships between hyperthyroidism and GERD or esophageal cancer. These results substantiate certain discoveries from previous observational studies on a causal level and provide insight into relevant genetic susceptibility factors.

Fostering Superior Characters: Development of Innovative Instruments for Critical Reasoning and Independent Character in the Realm of Science Topic

The purpose of this study was to develop a critical reasoning and independent character instrument on the topic of human blood circulation. The method used was research and development (R&D) with a 4D model (Define, Design, Develop, and Disseminate). The results showed that the validity value of the content of critical reasoning instruments obtained a final value of 0.97, while independent instruments obtained a value of 1, which was perfect. Judging from empirical validity, vital and independent reasoning instruments were declared valid because they had a value above 0.355 from 31 students tested. Critical and independent reasoning instruments were declared reliable. The Alpha Cronbach value >0.70 had good distinguishing power because the value of the Corrected Item-Total Correlation did not exceed the Alpha Cronbach value. Developing assessment instruments for a critical and independent character in human blood circulation for fifth-grade elementary students was successful, demonstrating high validity and reliability, and held the significant potential to enhance science education through technology integration.

Extended aerosol and surface characterization from S5P/TROPOMI with GRASP algorithm. Part II: Global validation and Intercomparison

This paper is the second part of companion papers describing the development of GRASP approach for aerosol and surface retrieval from Sentinel-5P/TROPOMI. Here we focus on the S5P/TROPOMI GRASP aerosol and surface products global validation and systematic intercomparison with other products from independent instruments and algorithms. Specifically, we have validated the S5P/TROPOMI GRASP, Suomi-NPP/VIIRS DB and MODIS/TERRA DT + DB aerosol products with the ground-based AERONET referenced measurements using the same methodology and intercompare the validation results. In addition, the global pixel-to-pixel intercomparisons of the aerosol products (AOD, fine/coarse mode AOD and SSA) are performed over different surfaces, i.e., ocean and land surface with different NDVIs. Besides, we compared the S5P/TROPOMI GRASP, MODIS MCD43 surface BRDF/albedo as well as OMI, GOME-2 and SCIAMACHY Lambertian-Equivalent Reflectivity (LER) albedo climatology developed by Royal Netherlands Meteorological Institute (KNMI) with the surface reference dataset generated based on the synergetic retrieval of AERONET and S5P/TROPOMI measurements. Finally, the intercomparisons of the surface BRDF and albedo datasets were performed globally at the UV, VIS, NIR and SWIR parts of the spectrum. Overall, generally good agreement was observed between independent aerosol and surface datasets with a high percentage of pixels satisfying the Optimal and Target requirements. We would emphasize two advantages for TROPOMI/GRASP aerosol and surface products: (i) it provides spectral AOD together with detailed aerosol properties, such as fine/coarse mode AOD, spectral AAOD and SSA at UV, VIS, NIR and SWIR wavelengths, which are important for constraining aerosol environmental and climate effects; (ii) the TROPOMI/GRASP aerosol and surface products are globally retrieved simultaneously in a fully consistent manner.

Associations of genetically predicted iron status with 24 gastrointestinal diseases and gut microbiota: a Mendelian randomization study.

Iron status has been implicated in gastrointestinal diseases and gut microbiota, however, confounding factors may influence these associations. We performed Mendelian randomization (MR) to investigate the associations of iron status, including blood iron content, visceral iron content, and iron deficiency anemia with the incidence of 24 gastrointestinal diseases and alterations in gut microbiota. Independent genetic instruments linked with iron status were selected using a genome-wide threshold of p = 5 × 10-6 from corresponding genome-wide association studies. Genetic associations related to gastrointestinal diseases and gut microbiota were derived from the UK Biobank, the FinnGen study, and other consortia. Genetically predicted higher levels of iron and ferritin were associated with a higher risk of liver cancer. Higher levels of transferrin saturation were linked to a decreased risk of celiac disease, but a higher risk of non-alcoholic fatty liver disease (NAFLD) and liver cancer. Higher spleen iron content was linked to a lower risk of pancreatic cancer. Additionally, higher levels of liver iron content were linked to a higher risk of NAFLD and liver cancer. However, certain associations lost their statistical significance upon accounting for the genetically predicted usage of cigarettes and alcohol. Then, higher levels of iron and ferritin were associated with 11 gut microbiota abundance, respectively. In a secondary analysis, higher iron levels were associated with lower diverticular disease risk and higher ferritin levels with increased liver cancer risk. Higher levels of transferrin saturation were proven to increase the risk of NAFLD, alcoholic liver disease, and liver cancer, but decrease the risk of esophageal cancer. MR analysis showed no mediating relationship among iron status, gut microbiota, and gastrointestinal diseases. This study provides evidence suggesting potential causal associations of iron status with gastrointestinal diseases and gut microbiota, especially liver disease.

Body shape from birth to adulthood is associated with skeletal development: A Mendelian randomization study

BackgroundObservational studies have shown that childhood obesity is associated with adult bone health but yield inconsistent results. We aimed to explore the potential causal association between body shape and skeletal development. MethodsWe used two-sample Mendelian randomization (MR) to estimate causal relationships between body shape from birth to adulthood and skeletal phenotypes, with exposures including placental weight, birth weight, childhood obesity, BMI, lean mass, fat mass, waist circumference, and hip circumference. Independent genetic instruments associated with the exposures at the genome-wide significance level (P < 5 × 10−8) were selected from corresponding large-scale genome-wide association studies. The inverse-variance weighted analysis was chosen as the primary method, and complementary MR analyses included the weighted median, MR-Egger, weighted mode, and simple mode. ResultsThe MR analysis shows strong evidence that childhood (β = −1.29 × 10−3, P = 8.61 × 10−5) and adulthood BMI (β = −1.28 × 10−3, P = 1.45 × 10−10) were associated with humerus length. Tibiofemoral angle was negatively associated with childhood BMI (β = −3.60 × 10−1, P = 3.00 × 10−5) and adolescent BMI (β = −3.62 × 10−1, P = 2.68 × 10−3). In addition, genetically predicted levels of appendicular lean mass (β = 1.16 × 10−3, P = 1.49 × 10−13), whole body fat mass (β = 1.66 × 10−3, P = 1.35 × 10−9), waist circumference (β = 1.72 × 10−3, P = 6.93 × 10−8) and hip circumference (β =1.28 × 10−3, P = 4.34 × 10−6) were all associated with tibia length. However, we found no causal association between placental weight, birth weight and bone length/width. ConclusionsThis large-scale MR analysis explores changes in growth patterns in the length/width of major bone sites, highlighting the important role of childhood body shape in bone development and providing insights into factors that may drive bone maturation.

No causal relationship between glucose and inflammatory bowel disease: a bidirectional two-sample mendelian randomization study

BackgroundAssociation between glucose and inflammatory bowel disease (IBD) was found in previous observational studies and in cohort studies. However, it is not clear whether these associations reflect causality. Thus, this study investigated whether there is such a causal relation between elevated glucose and IBD, Crohn’s disease (CD) and ulcerative colitis (UC).MethodsWe performed a two-sample Mendelian Randomization (MR) with the independent genetic instruments identified from the largest available genome-wide association study (GWAS) for IBD (5,673 cases; 213,119 controls) and its main subtypes, CD and UC. Summarized data for glucose which included 200,622 cases and glycemic traits including HbA1c and type 2 diabetes(T2DM) were obtained from different GWAS studies. Primary and secondary analyses were conducted by preferentially using the radial inverse-variance weighted (IVW) approach. A number of other meta-analysis approach and sensitivity analyses were carried out to assess the robustness of the results.ResultsWe did not find a causal effect of genetically predicted glucose on IBD as a whole (OR 0.858; 95% CI 0.649–1.135; P = 0.286). In subtype analyses glucose was also suggestively not associated with Crohn’s disease (OR 0.22; 95% CI 0.04-1.00; P = 0.05) and ulcerative colitis (OR 0.940; 95% CI 0.628–1.407; P = 0.762). In the other direction, IBD and its subtypes were not related to glucose and glycemic traits.ConclusionsThis MR study is not providing any evidence for a causal relationship between genetically predicted elevated glucose and IBD as well as it’s subtypes UC and CD. Regarding the other direction, no causal associations could be found. Future studies with robust genetic instruments are needed to confirm this conclusion.

Interannual Variability of Water and Heat Fluxes in a Woodland Savanna (Cerrado) in Southeastern Brazil: Effects of Severe Drought and Soil Moisture

The Brazilian Cerrado biome is known for its high biodiversity, and the role of groundwater recharge and climate regulation. Anthropogenic influence has harmed the biome, emphasizing the need for science to understand its response to climate and reconcile economic exploration with preservation. Our work aimed to evaluate the seasonal and interannual variability of the surface energy balance in a woodland savanna (Cerrado) ecosystem in southeastern Brazil over a period of 19 years, from 2001 to 2019. Using field micrometeorological measurements, we examined the variation in soil moisture and studied its impact on the temporal pattern of energy fluxes to distinguish the effects during rainy years compared to a severe drought spell. The soil moisture measures used two independent instruments, cosmic ray neutron sensor CRNS, and FDR at different depths. The measures were taken at the Pé de Gigante (PEG) site, in a region of well-defined seasonality with the dry season in winter and a hot/humid season in summer. We gap-filled the energy flux measurements with a calibrated biophysical model (SiB2). The long-term averages for air temperature and precipitation were 22.5 °C and 1309 mm/year, respectively. The net radiation (Rn) was 142 W/m2, the evapotranspiration (ET) and sensible heat flux (H) were 3.4 mm/d and 52 W/m2, respectively. Soil moisture was marked by a pronounced negative anomaly in the 2014 year, which caused an increase in the Bowen ratio and a decrease in Evaporative fraction, that lasted until the following year 2015 during the dry season, despite the severe meteorological drought of 2013/2014 already ending, which was corroborated by the two independent measurements. The results showed the remarkable influence of precipitation and soil moisture on the interannual variability of the energy balance in this Cerrado ecosystem, aiding in understanding how it responds to strong climate disturbances.

Producing peripheries: morphology and habitability in the conurbations of Cuenca, Ecuador

The expansion of Latin American intermediate cities has left irregular and discontinuous occupation patterns in their peripheral territories. In appearance, the configurations of the urban edges do not have relevant differences. In fact, each morphological structure is heterogeneous and has its own behaviors, different occupation motivations, and diverse resulting consolidated models. In Cuenca, Ecuador, these diffuse zones between the urban and rural limits are marked by segregation dynamics and dependence on the consolidated center and have the lowest quality-of-life indexes in the city. In this context, the objective of the research was to find a possible relationship between the types of peripheral morphologies and the levels of urban habitability of four city urban centers, using a quantitative methodological design with a two-stage correlational scope. Initially, urban morphologies were classified, and the habitability levels were rated separately, applying independent instruments. Then, the results were cross-checked to describe possible links between variables. The findings highlight significant disparities in habitability between conurbations and define an apparent direct correlation between the two dimensions of analysis.

Rheumatoid arthritis and the risk of chronic kidney diseases: a Mendelian randomization study.

The extra-articular lesions of rheumatoid arthritis (RA) are reported to involve multiple organs and systems throughout the body, including the heart, kidneys, liver, and lungs. This study assessed the potential causal relationship between RA and the risk of chronic kidney diseases (CKDs) using the Mendelian randomization (MR) analysis. Independent genetic instruments related to RA and CKD or CKD subtypes at the genome-wide significant level were chosen from the publicly shared summary-level data of genome-wide association studies (GWAS). Then, we obtained some single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs), which are associated with RA in individuals of European origin, and had genome-wide statistical significance (p5 × 10-8). The inverse-variance weighted (IVW) method was the main analysis method in MR analysis. The other methods, such as weighted median, MR-Egger, simple mode, and weighted mode were used as supplementary sensitivity analyses. Furthermore, the levels of pleiotropy and heterogeneity were assessed using Cochran's Q test and leave-one-out analysis. Furthermore, the relevant datasets were obtained from the Open GWAS database. Using the IVW method, the main method in MR analysis, the results showed that genetically determined RA was associated with higher risks of CKD [odds ratio (OR): 1.22, 95% confidence interval (CI) 1.13-1.31; p < 0.001], glomerulonephritis (OR: 1.23, 95% CI 1.15-1.31; p < 0.000), amyloidosis (OR = 1.43, 95% CI 1.10-1.88, p < 0.001), and renal failure (OR = 1.18, 95% CI 1.00-1.38, p < 0.001). Then, using multiple MR methods, it was confirmed that the associations persisted in sensitivity analyses, and no pleiotropy was detected. The findings revealed a causal relationship between RA and CKD, including glomerulonephritis, amyloidosis, and renal failure. Therefore, RA patients should pay more attention to monitoring their kidney function, thus providing the opportunity for earlier intervention and lower the risk of progression to CKDs.

Trends and drivers of anthropogenic NOx emissions in China since 2020

Nitrogen oxides (NOx), significant contributors to air pollution and climate change, form aerosols and ozone in the atmosphere. Accurate, timely, and transparent information on NOx emissions is essential for decision-making to mitigate both haze and ozone pollution. However, a comprehensive understanding of the trends and drivers behind anthropogenic NOx emissions from China—the world's largest emitter—has been lacking since 2020 due to delays in emissions reporting. Here we show a consistent decline in China's NOx emissions from 2020 to 2022, despite increased fossil fuel consumption, utilizing satellite observations as constraints for NOx emission estimates through atmospheric inversion. This reduction is corroborated by data from two independent spaceborne instruments: the TROPOspheric Monitoring Instrument (TROPOMI) and the Ozone Monitoring Instrument (OMI). Notably, a reduction in transport emissions, largely due to the COVID-19 lockdowns, slightly decreased China's NOx emissions in 2020. In subsequent years, 2021 and 2022, reductions in NOx emissions were driven by the industry and transport sectors, influenced by stringent air pollution controls. The satellite-based inversion system developed in this study represents a significant advancement in the real-time monitoring of regional air pollution emissions from space.

Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease.

Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease. The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D. The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.226 [95% CI, 1.160-1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively). The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.

Результаты сравнения длин линий на базисе пространственном эталонном СГУГиТ

The results of line lengths comparison on the spatial reference basis (SRB) of SGUGiT, carried out according to the program in all combinations measurements in the forward direction from point BI01 to point BI10 in spring and summer of 2021 and 2023 using total station Leica TM30, as well as, in the same seasons of 2023 done by laser tracker Leica AT403 are given. Based on the analysis of multiple measurements of each section of the basis (at least 30 ones), the standard deviation and uncertainty were calculated. Meanwhile, at the extreme points of the base section, meteorological parameters (temperature, pressure and relative humidity) were recorded by two independent instruments, which were then entered immediately when metering with a Leica TM 30 electronic total station. In the case of the Leica AT403 laser tracker, they were automatically taken into account in specialized software management and processing of Spatial Analyzer measurement data. Due to the research results, it was found out that the expanded uncertainty in measuring the lengths of the basic lines in the range from 12 to 192 m on the WPT using a Leica AT403 laser tracker and a Leica TM30 electronic total station, taking into account the accepted errors that affect the final result, is no more than 1,4 mm, and the maximum contribution to the mistake in determining line lengths is made by the standard uncertainty estimated by type B. In addition, seasonal fluctuations in the position of individual basis points are observed

Association between non-scarring alopecia and hypothyroidism: a bidirectional two-sample Mendelian randomization study.

Non-scarring alopecia is typically represented by two main types: alopecia areata (AA) and androgenetic alopecia (AGA). While previous observational studies have indicated a link between non-scarring alopecia and hypothyroidism, the precise causal relationship remains uncertain. To determine the potential links between non-scarring alopecia and hypothyroidism, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. We used independent genetic instruments from the FinnGen consortium for AA (682 cases, 361,140 controls) and AGA (195 cases, 201,019 controls) to investigate the association with hypothyroidism in the UK Biobank study (22,687 cases, 440,246 controls). The primary analysis was performed using the inverse variance-weighted method. Complementary approaches were employed to evaluate the pleiotropy and heterogeneity. Genetically predicted AA exhibited a positive causal effect on hypothyroidism (odds ratio [OR], 1.0017; 95% confidence interval [CI], 1.0004-1.0029; P = 0.0101). Additionally, hypothyroidism was found to be strongly correlated with an increase in the risk of AA (OR, 45.6839; 95% CI, 1.8446-1131.4271, P = 0.0196). However, no causal relationship was demonstrated between AGA and hypothyroidism. A sensitivity analysis validated the integrity of these causal relationships. This MR study supports a bidirectional causal link between AA and hypothyroidism. Nevertheless, additional research is needed to gain a more thorough comprehension of the causal relationship between non-scarring alopecia and hypothyroidism.

Maternal plasma cortisol’s effect on offspring birth weight: a Mendelian Randomisation study

BackgroundObservational 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.

Mendelian randomization analysis of atopic dermatitis and esophageal cancer in East Asian and European populations

BackgroundEmerging observational studies showed an association between atopic dermatitis (AD) and gastrointestinal cancers. However, it remains unclear whether this association is causal, particularly in the case of cancers like esophageal cancer, which exhibit ancestral genetic traits. MethodsTo assess the potential causal relationship between AD and esophageal cancer across diverse ancestral backgrounds, we conducted a 2-sample Mendelian randomization study. Independent genetic instruments for AD from the FinnGen consortium (N case = 7024 and N control = 198 740), BioBank Japan (N case = 2385 and N control = 209 651) and Early Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium (N case = 18 900 and N control = 84 166, without the 23andMe study) were used to investigate the association with esophageal cancer in the UK Biobank study (N case = 740 and N control = 372 016) and BioBank Japan esophageal cancer sample (N case = 1300 and N control = 197 045). ResultsWhen esophageal cancer extracted from East Asian ancestry was used as a outcome factor, AD data extracted from BioBank Japan (OR = 0.90, 95% CI: 0.83–0.98), FinnGen consortium (OR = 0.86, 95% CI: 0.77–0.96), and EAGLE consortium (OR = 0.92, 95% CI: 0.81–1.06) were negatively associated with esophageal cancer susceptibility. However, AD as a whole did not show an association with esophageal cancer from European ancestry. ConclusionThis study provides support for a causal relationship between AD and esophageal cancer in East Asian populations but not between AD and esophageal cancer from European ancestry. The specific associations between esophageal cancer and AD appear to exhibit significant disparities between the East Asian and European regions.

A Positive Causal Effect of Shrimp Allergy on Major Depressive Disorder Mediated by Allergy- and Immune-Related Pathways in the East Asian Population.

Observational studies have implied a potential correlation between allergic diseases and major depressive disorder (MDD). However, the relationship is still inconclusive as it is likely to be interfered with by substantial confounding factors and potential reverse causality. The present study aimed to investigate causal correlation of the two diseases by a Mendelian randomization (MR) study and further elucidate the underlying molecular mechanisms. With the biggest summary datasets of a genome-wide association study (GWAS) in the East Asian population, we conducted a two-sample, bidirectional MR study to assess the causal correlation between shrimp allergy (SA) and MDD. Subsequently, we identified the pleiotropic genes' susceptibility to the two diseases at whole-genome and tissue-specific levels, respectively. Enriched GO sets and KEGG pathways were also discovered to elucidate the potential underlying mechanisms. With the most suitable MR method, SA was identified as a causal risk factor for MDD based on three different groups of independent genetic instruments, respectively (p < 2.81 × 10-2). In contrast, we did not observe a significant causal effect of MDD on SA. The GWAS-pairwise program successfully identified seven pleiotropic genetic variants (PPA3 > 0.8), indicating that the two diseases indeed have a shared genetic basis. At a whole-genome level, the MAGMA program identified 44 pleiotropic genes, which were enriched in allergy-related pathways, such as antigen processing and presentation pathway (p = 1.46 × 10-2). In brain-specific tissue, the S-MultiXcan program found 17 pleiotropic genes that were significantly enriched in immune-related pathways and GO sets, including asthma-related pathway, T-cell activation-related, and major histocompatibility complex protein-related GO sets. Regarding whole-blood tissue, the program identified six pleiotropic genes that are significantly enriched in tolerance induction-related GO sets. The present study for the first time indicated a significant causal effect of SA on the occurrence of MDD, but the reverse was not true. Enrichment analyses of pleiotropic genes at whole-genome and tissue-specific levels implied the involvement of allergy and immune-related pathways in the shared genetic mechanism of the two diseases. Elucidating the causal effect and the acting direction may be beneficial in reducing the incidence rate of MDD for the massive group of SA patients in the East Asian region.

Causal Associations Between Plasma Protein Levels and Alzheimer Disease

AbstractBackgroundThe aim of this study was to infer causal relationships between protein levels measured in blood and the risk of late‐onset Alzheimer disease (AD).MethodTwo‐sample Mendelian randomization (MR) was used to infer the causal effect of protein levels on AD risk. Summary statistics from genome‐wide association studies (GWAS) for 4,907 SomaScan aptamers (measuring 4,719 proteins) from Ferkingstad et al. (2021) in 35,559 Icelanders (average age = 55±17years), and for AD GWAS from Bellenguez et al. (2022). Instruments for exposures were selected at p &lt; 5×10−8 and p &lt; 5×10−6 thresholds respectively for the main and sensitivity analyses. Instruments were pruned for linkage disequilibrium (r2 &lt; 0.0001) to ensure selection of independent instruments. Because APOE is highly pleiotropic and exposure effect size is hypothesized by MR not to be larger than the outcome (Steiger filtering), thus variants within ±1MB from APOE were removed in the MR‐analysis. Two tests were considered: Inverse‐Variance‐Weighted and Weighted‐Median, which allows robust MR estimates even when some invalid instruments are included.ResultAmong known AD‐GWAS genes, TREM2, PILRA, ACE, CR1, and BIN1 protein levels were associated with AD. Proteins without prior AD‐GWAS links were also found to be associated with AD including: PPBP, NRP2, AZGP2, and TNFSF13B/BAFF (Figures 1&amp;2). Interestingly, APOE and KLOTHO levels were not associated with AD (Figures 3&amp;4), though increased APOE level significantly associated with increase AD risk when including cis‐APOE variants at p &lt; 5×10−6 (Figure 5).ConclusionOur study informs the directionality of association between certain plasma protein levels and AD risk, and prioritizes candidate proteins to be considered for AD drug development.