A Transethnic Mendelian Randomization Study Identifies Causality of Obesity on Risk of Psoriasis.
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ABSTRACT:
SUBMITTER: Ogawa K
PROVIDER: S-EPMC7028352 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
Publications
A Transethnic Mendelian Randomization Study Identifies Causality of Obesity on Risk of Psoriasis.
Ogawa Kotaro K Stuart Philip E PE Tsoi Lam C LC Suzuki Ken K Nair Rajan P RP Mochizuki Hideki H Elder James T JT Okada Yukinori Y
The Journal of investigative dermatology 20181205 6
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Project description:BackgroundMany observational studies have identified a link between unsaturated fatty acids and psoriasis. However, they contain reverse causality and confounding factors, and there is no definite causal study between unsaturated fatty acids and psoriasis.ObjectivesAnalysis of causality between unsaturated fatty acids and psoriasis by Mendelian randomization.MethodsWe used IEU Open GWAS Project, omega-3 PUFA and omega-6 PUFA data from 114,999 subjects, MUFA data from 13,535 subjects, and psoriasis data from 4,510 cases and 212,242 controls were included. We employed the inverse-variance weighted (IVW) method as the primary analytical approach and four additional MR methods. Moreover, we performed heterogeneity and horizontal pleiotropy assessments using Cochrane's Q and MR-Egger intercept tests, respectively. Finally, we performed sensitivity analyses to enhance our findings' precision and veracity.ResultsIVW results showed no causal effect of omega-3 PUFA on psoriasis (p = 0.334; OR, 0.909; 95% CI, 0.748-1.104), omega-6 PUFA cause psoriasis (p = 0.046; OR, 1.174; 95% CI, 1.003-1.374), MUFA cause psoriasis (p = 0.032; OR, 1.218; 95% CI, 1.018-1.457), no causal effect of omega-3 PUFA in psoriasis (p = 0.695; OR, 0.989; 95% CI, 0.937-1.044), no causal effect of omega-6 PUFA in psoriasis (p = 0.643; OR, 1.013; 95% CI, 0.960-1.068), psoriasis is not causal to MUFA (p = 0.986; OR, 1.000; 95% CI, 0.949-1.055). Heterogeneity, horizontal pleiotropy, and sensitivity analyses showed reliable results.ConclusionWe found that circulating omega-6 PUFA and MUFA cause psoriasis, while omega-3 PUFA do not. Treatments that lower circulating omega-6 PUFA and MUFA are effective in psoriasis. After a better understanding of fatty acid intake and circulation, the population can be advised to regulate their diet.
| S-EPMC10884181 | biostudies-literature
Project description:BackgroundFrailty is associated with a variety of diseases, but the relationship between frailty and psoriasis remains unclear.MethodsFirst, we conducted a two-sample Mendelian randomization based on genome-wide association studies (GWAS) to investigate genetic causality between frailty index and common diseases in dermatology. Inverse variance weighted was used to estimate causality. Second, expression quantitative trait locus (eQTLs) analysis was conducted to identify the genes affected by Single nucleotide polymorphisms (SNPs). Third, we performed function and pathway enrichment, transcriptome-wide association studies (TWAS) analysis based on eQTLs.ResultsIt was shown that the rise of frailty index could increase the risk of psoriasis (IVW, beta = 0.916, OR = 2.500, 95%CI:1.418-4.408, p = 0.002) through Mendelian randomization (MR), and there was no heterogeneity and pleiotropy. There was no causality between the frailty index and other common diseases in dermatology. We found 31 eQTLs based on strongly correlated SNPs in the causality. TWAS analysis found that the expressions of four genes were closely related to psoriasis, including HLA-DQA1, HLA-DQA2, HLA-DRB1 and HLA-DQB1.ConclusionIt suggested that the frailty index had a significant positive causality on the risk of psoriasis, which was well documented by combined genomic, transcriptome, and proteome analyses.
| S-EPMC10905529 | biostudies-literature
Project description:Psoriasis mimics uric acid in terms of inflammation, but the association has not been well defined. This study aimed to identify the causal link between serum uric acid (SUA) and psoriasis in an observational study using the National Health and Nutrition Examination Survey (NHANES, 2004-2006, and 2011-2014) and transethnic Mendelian randomization (MR) analyses. We utilized weighted multivariable-adjusted logistic regression and transethnic MR in European and East Asian populations to assess the association. Inverse variance weighted (IVW) was the main analysis. To test the robustness and pleiotropy, further sensitivity analyses were also conducted. Weighted regression analysis suggested that SUA positively related to psoriasis risk (OR = 1.339, 95% CI: 1.092-1.642, P = 0.006) in women. For all participants and males, neither association was significant. IVW showed that SUA levels were not significantly associated with psoriasis in Europeans (OR = 1.099, 95% CI: 0.963-1.254, P = 0.159) or East Asians (OR = 1.297, 95% CI: 0.576-2.918, P = 0.528). Furthermore, sensitivity analyses confirmed the robustness of the present MR results. In females, SUA and psoriasis were significantly correlated; findings from transethnic MR analysis did not indicate a causal relationship between SUA and psoriasis.
| S-EPMC11530690 | biostudies-literature
Project description:BackgroundWhether obesity is a cause or consequence of low physical activity levels and more sedentary time has not yet been fully elucidated. Better instrumental variables and a more thorough consideration of potential confounding variables that may influence the causal inference between physical activity and obesity are needed.MethodsLeveraging results from our recent genome-wide association study for leisure time moderate-to-vigorous intensity (MV) physical activity and screen time, we here disentangle the causal relationships between physical activity, sedentary behavior, education-defined by years of schooling-and body mass index (BMI), using multiple univariable and multivariable Mendelian Randomization (MR) approaches.ResultsUnivariable MR analyses suggest bidirectional causal effects of physical activity and sedentary behavior with BMI. However, multivariable MR analyses that take years of schooling into account suggest that more MV physical activity causes a lower BMI, and a higher BMI causes more screen time, but not vice versa. In addition, more years of schooling causes higher levels of MV physical activity, less screen time, and lower BMI.ConclusionsIn conclusion, our results highlight the beneficial effect of education on improved health and suggest that a more physically active lifestyle leads to lower BMI, while sedentary behavior is a consequence of higher BMI.
| S-EPMC10689836 | biostudies-literature
Project description:Objectives Mendelian randomization (MR) was used to estimate the causal relationship between body mass index (BMI), ever smoked, heart failure, alcohol intake frequency, inflammatory bowel disease (IBD), and pulmonary embolism (PE). This study aimed to investigate whether there is a causal relationship between BMI, the presence of smoking, heart failure, frequency of alcohol intake, IBD, and PE. Methods Pooled data on PE from a published GWAS meta-analysis involving approximately 461,164 participants of European ancestry were selected. A publicly available pooled dataset of BMI (461,460), ever smokers (461,066), heart failure (977,323), IBD (75,000), and frequency of alcohol intake (462,346) was used from another independent GWAS. MR was performed using established analysis methods, including Wald ratios, inverse variance weighted (IVW), weighted median (WM), and MR-Egger. Also, the final expansion was validated with multivariate MR. Results In the IVW model, genetically elevated BMI was causally associated with PE [OR = 1.002, 95% CI (1.001, 1004), P = 0.039]. Cochran’s Q test was used to detect heterogeneity in the MR-Egger analysis (P = 0.576). Therefore, the effect of gene-level heterogeneity was not considered. In the MR analysis of other risk factors, we observed genes for ever smoking [IVW OR = 1.004, 95% CI (0.997, 1.012)], heart failure [IVW OR = 0.999, 95% CI (0.996, 1.001)], IBD [IVW OR = 1.000, 95% CI (0.999, 1.001)], and frequency of alcohol intake [IVW OR = 1.002, 95% CI (1.000, 1.004)] were not causally associated with PE. Analysis using multivariate MR expansion showed no causal effect of BMI on PE considering the effect of height as well as weight (P = 0.926). Conclusion In European populations, a causal relationship exists between BMI and PE: increased BMI leads to PE. In contrast, ever smoking, heart failure, frequency of alcohol intake, and IBD are not directly associated with PE. There was no causal effect of BMI with PE in multivariate Mendelian randomized analysis.
| S-EPMC9996005 | biostudies-literature
Project description:BackgroundWhilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship.MethodsWe performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset.ResultsOur systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding).ConclusionsOur comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.
| S-EPMC7268455 | biostudies-literature
Project description:Background and aimTo date, the association between glucocorticoid use and the risk of pancreatitis remains controversial. The aim of this study was the investigation of this possible relationship.MethodsWe carried out a two-sample Mendelian randomization (MR) analysis using GWAS data from European ancestry, East Asian descendants and the FinnGen Biobank Consortium to evaluate this potential causal relationship. Genetic variants associated with glucocorticoid use were selected based on genome-wide significance (p < 5×10-8).ResultsOur MR analysis of European ancestry data revealed no significant causal relationship between glucocorticoid use and AP (IVW: OR=1.084, 95% CI= 0.945-1.242, P=0.249; MR-Egger: OR=1.049, 95% CI= 0.686-1.603, P=0.828; weighted median: OR=1.026, 95% CI= 0.863-1.219, P=0.775) or CP (IVW: OR=1.027, 95% CI= 0.850-1.240, P=0.785; MR-Egger: OR= 1.625, 95% CI= 0.913-2.890, P= 0.111; weighted median: OR= 1.176, 95% CI= 0.909-1.523, P= 0.218). Sensitivity analyses, including MR-Egger and MR-PRESSO, indicated no evidence of pleiotropy or heterogeneity, confirming the robustness of our findings. Multivariable MR analysis adjusted for alcohol consumption, BMI, cholelithiasis and C-reactive protein levels supported these findings. Replicated analysis was performed on datasets from the FinnGen Biobank Consortium and East Asian descendants, and similar results were obtained.ConclusionsThis MR analysis suggests that there is no causal association between glucocorticoid use and the risk of pancreatitis.
| S-EPMC11363070 | biostudies-literature
Project description: Not available
| S-EPMC10759661 | biostudies-literature
Project description:BackgroundStudies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed.MethodsA cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR.ResultsIn total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR.ConclusionsIn a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
| S-EPMC8425654 | biostudies-literature
Project description:BackgroundRheumatoid arthritis is a common rheumatic disease, and its onset is closely related to genetic and environmental factors, however, the relationship between air pollution and RA is still hotly debated. Further investigation of the relationship between air pollution and rheumatoid arthritis is conducive to a comprehensive understanding of the risk factors of the disease, providing certain value for the clinical prevention and treatment of RA.MethodsWe used a Two-Sample Mendelian Randomization approach, integrating the large-scale public genomewide association study, to assess the genetically predicted causal effect of air pollution (including: PM2.5, PM2.5-10, PM10, nitrogen dioxide, nitrogen oxides) on RA in European and European East Asian populations, respectively. Indicators related to air pollution (2,505 individuals to 423,796 individuals), including European and East Asian populations were obtained from the Integrative Epidemiology Unit open GWAS project. Published East Asian RA data were also obtained from the IEU open GWAS project (212,453 individuals), while large-scale publicly available European RA data were obtained from finngen R10 (13,621 cases and 262,844 controls). Inverse variance weighting was used as the primary analytical method, complemented by MR-egger, Weighed median, and Weighted mode results. Cochran Q tested for heterogeneity, and MR-Egger regression analyses were performed to test for multiplicity. leave-one-out analysis allowed for the robustness and reliability were assessed.ResultsNo statistically significant effects of PM2.5, PM2.5-10, PM10, nitrogen dioxide, nitrogen oxides and RA were observed in either European or East Asian populations. Results from European data: PM2.5 (IVW OR: 0.71; 95% CI: 0.27-1.91; p = 0.498; number of SNPs: 5), PM2.5-10 (IVW OR: 1.20; 95% CI: 0.61-2.40; p = 0.596; number of SNPs: 15), PM10 (IVW OR: 1.69; 95% CI: 0.84-3.39; p = 0.142; number of SNPs: 9), nitrogen dioxide (IVW OR: 3.88; 95% CI: 0.19-77.77; p = 0.375; number of SNPs: 2), nitrogen oxides (IVW OR: 0.51; 95% CI: 0.16-1.67; p = 0.268; number of SNPs: 4). East Asian data results: PM2.5 (IVW OR: 1.16; 95% CI: 0.98-1.38; p = 0.086; number of SNPs: 4), PM2.5-10 (IVW OR: 1.14; 95% CI: 0.95-1.38; p = 0.166; number of SNPs: 2), PM10 (IVW OR: 0.95; 95% CI: 0.81-1.11; p = 0.503; number of SNPs: 3), nitrogen dioxide (IVW OR: 0.87; 95% CI: 0.76-1.00; p = 0.051; number of SNPs: 6), nitrogen oxides (IVW OR: 0.96; 95% CI: 0.82-1.14; p = 0.671; number of SNPs: 3). No signs of pleiotropy or heterogeneity were observed in the MR-Egger intercept, MR-PRESSO and Cochrane's Q (p>0.05). In addition, no outliers were found in the MR-PRESSO analysis. The results were further validated by leave-one-out tests, confirming the robustness of the findings.ConclusionsWe performed transethnic MR analysis suggesting that there may not be a genetically predicted causal relationship between air pollution and RA.
| S-EPMC11421788 | biostudies-literature