Micronutrient-Associated Single Nucleotide Polymorphism and Mental Health: A Mendelian Randomization Study
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PROVIDER: S-EPMC11243241 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:BackgroundObservational studies have shown an association between higher bilirubin levels and improved respiratory health outcomes. Targeting higher bilirubin levels has been proposed as a novel therapeutic strategy in COPD. However, bilirubin levels are influenced by multiple intrinsic and extrinsic factors, and these observational studies are prone to confounding. Genetic analyses are one approach to overcoming residual confounding in observational studies.ObjectivesTo test associations between a genetic determinant of bilirubin levels and respiratory health outcomes.MethodsCOPDGene participants underwent genotyping at the baseline visit. We confirmed established associations between homozygosity for rs6742078 and higher bilirubin, and between higher bilirubin and decreased risk of acute respiratory events within this cohort. For our primary analysis, we used negative binomial regression to test associations between homozygosity for rs6742078 and rate of acute respiratory events.Results8,727 participants (n = 6,228 non-Hispanic white and 2,499 African American) were included. Higher bilirubin was associated with decreased rate of acute respiratory events [incidence rate ratio (IRR) 0.85, 95% CI 0.75 to 0.96 per SD increase in bilirubin intensity]. We did not find significant associations between homozygosity for rs6742078 and acute respiratory events (IRR 0.94, 95% CI 0.70 to 1.25 for non-Hispanic white and 1.09, 95% CI 0.91 to 1.31 for African American participants).ConclusionsA genetic determinant of higher bilirubin levels was not associated with better respiratory health outcomes. These results do not support targeting higher bilirubin levels as a therapeutic strategy in COPD.
| S-EPMC10357606 | biostudies-literature
Project description:BackgroundInterleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous.MethodsAn inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study.ResultsThe selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results.ConclusionTherefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.
| S-EPMC10556766 | biostudies-literature
Project description:ImportanceObservational studies have demonstrated consistent protective effects of higher educational attainment (EA) on the risk of suffering mental health conditions (MHC). Determining whether these beneficial effects are causal is challenging given the potential role of dynastic effects and demographic factors (assortative mating and population structure) in this association.ObjectiveTo evaluate to what extent the relationship between EA and various MHC is independent from dynastic effects and demographic factors.DesignWithin-sibship Mendelian randomization (MR) study.SettingOne-sample MR analyses included participants' data from the Trøndelag Health Study (HUNT, Norway) and UK Biobank (United Kingdom). For two-sample MR analyses we used summary statistics from publicly available genome-wide-association-studies.Participants61 880 siblings (27 507 sibships).ExposureYears of education.Main outcomesScores for symptoms of anxiety, depression and neuroticism using the Hospital Anxiety Depression Scale (HADS), the 7-item Generalized Anxiety Disorder Scale (GAD-7), the 9-item Patient Health Questionnaire (PHQ-9), and the Eysenck Personality Questionnaire, as well as self-reported consumption of psychotropic medication.ResultsOne standard deviation (SD) unit increase in years of education was associated with a lower symptom score of anxiety (-0.20 SD [95%CI: -0.26, -0.14]), depression (-0.11 SD [-0.43, 0.22]), neuroticism (-0.30 SD [-0.53, -0.06]), and lower odds of psychotropic medication consumption (OR: 0.60 [0.52, 0.69]). Estimates from the within-sibship MR analyses showed some attenuation, which however were suggestive of a causal association (anxiety: -0.17 SD [-0.33, -0.00]; depression: -0.18 SD [-1.26, 0.89]; neuroticism: -0.29 SD [-0.43, -0.15]); psychotropic medication consumption: OR, 0.52 [0.34, 0.82]).Conclusions and relevanceAssociations between EA and MHC in adulthood, although to some extend explained by dynastic effects and demographic factors, overall remain robust, indicative of a causal effect. However, larger studies are warranted to improve statistical power and further validate our conclusions.
| S-EPMC11326327 | biostudies-literature
Project description: Not available
| S-EPMC10940541 | biostudies-literature
Project description:Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one- and two- sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß: -0.15, 95%CI: -0.26, -0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being.
| S-EPMC8643500 | biostudies-literature
Project description:Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).
| S-EPMC4850434 | biostudies-other
Project description:BackgroundMental disorders account for an enormous global burden of disease, and has been associated with disturbed iron metabolism in observational studies. However, such associations are inconsistent and may be attributable to confounding from environmental factors. This study uses a two-sample Mendelian randomization (MR) analysis to investigate whether there is any causal effect of systemic iron status on risk of 24 specific mental disorders.MethodsGenetic variants with concordant relations to 4 biomarkers of iron status (serum iron, ferritin, transferrin saturation, and transferrin) were obtained from a genome-wide association study performed by the Genetics of Iron Status (GIS) consortium. Summary-level data for mental disorders were obtained from the UK Biobank. An inverse-variance weighted (IVW) approach was used for the main analysis, and the simple median, weighted median and MR-Egger methods were used in sensitivity analyses.ResultsGenetically predicted serum iron, ferritin, and transferrin saturation were positively associated with depression and psychogenic disorder, and inversely associated with gender identity disorders. A higher transferrin, indicative of lower iron status, was also associated with increased risk of gender identity disorders and decreased risk of psychogenic disorder. Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy.ConclusionOur findings offer a novel insight into mental health, highlighting a detrimental effect of higher iron status on depression and psychogenic disorder as well as a potential protective role on risk of gender identity disorders. Further studies regarding the underlying mechanisms are warranted for updating preventative strategies.
| S-EPMC9797506 | biostudies-literature
Project description:Background: Sepsis, a global health challenge, necessitates a nuanced understanding of modifiable factors for effective prevention and intervention. The role of trace micronutrients in sepsis pathogenesis remains unclear, and their potential connection, especially with genetic influences, warrants exploration. Methods: We employed Mendelian randomization (MR) analyses to assess the causal relationship between genetically predicted blood levels of nine micronutrients (calcium, β-carotene, iron, magnesium, phosphorus, vitamin C, vitamin B6, vitamin D, and zinc) and sepsis susceptibility, severity, and subtypes. The instrumental variables for circulating micronutrients were derived from nine published genome-wide association studies (GWAS). In the primary MR analysis, we utilized summary statistics for sepsis from two independent databases (UK Biobank and FinnGen consortium), for initial and replication analyses. Subsequently, a meta-analysis was conducted to merge the results. In secondary MR analyses, we assessed the causal effects of micronutrients on five sepsis-related outcomes (severe sepsis, sepsis-related death within 28 days, severe sepsis-related death within 28 days, streptococcal septicaemia, and puerperal sepsis), incorporating multiple sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. Results: The study revealed a significant causal link between genetically forecasted zinc levels and reduced risk of severe sepsis-related death within 28 days (odds ratio [OR] = 0.450; 95% confidence interval [CI]: 0.263, 0.770; p = 3.58 × 10-3). Additionally, suggestive associations were found for iron (increased risk of sepsis), β-carotene (reduced risk of sepsis death) and vitamin C (decreased risk of puerperal sepsis). No significant connections were observed for other micronutrients. Conclusion: Our study highlighted that zinc may emerges as a potential protective factor against severe sepsis-related death within 28 days, providing theoretical support for supplementing zinc in high-risk critically ill sepsis patients. In the future, larger-scale data are needed to validate our findings.
| S-EPMC10904592 | biostudies-literature
Project description:(1) Background: Estimating the causal association between nutrient intake, as a modifiable risk factor, and stroke risk is beneficial for the prevention and management of stroke. However, observational studies are unavoidably influenced by confounding factors and reverse causation. (2) Methods: We performed a two-sample Mendelian randomization (MR) to estimate the effects of nutrient intake on stroke risk. Summary statistics for nutrients, including 4 macronutrients and 14 micronutrients, were derived from 15 genome-wide association studies (GWAS). Data on stroke and its subtypes were sourced from the MEGASTROKE consortium. (3) Results: Genetically predicted magnesium levels, as the protective factors, were significantly associated with a lower risk of cardioembolic stroke (OR: 0.011, 95% CI: 0-0.25, p-value: 0.005) in the IVW method. Additionally, vitamin C reduced the risk of cardioembolic stroke (OR: 0.759, 95% CI: 0.609-0.946, p-value: 0.014) and vitamin B9 reduced the risk of small vessel stroke (OR: 0.574, 95% CI: 0.393-0.839, p-value: 0.004) with the IVW method. However, the association of vitamin B6 with an increased risk of large-artery stroke (OR: 1.546, 95% CI: 1.009-2.37, p-value: 0.046) in the Wald ratio method should be interpreted cautiously due to the limited number of SNPs. There was also suggestive evidence that magnesium might decrease the risk of both any stroke and ischemic stroke. (4) Conclusions: Our MR analysis highlights the protective roles of magnesium, vitamin C, and vitamin B9 in stroke prevention, making them key targets for public health strategies. However, the findings related to vitamin B6 are less certain and require further validation.
| S-EPMC11397079 | biostudies-literature
Project description:Primary Objective:
Correlation of the skin and/or eye toxicity grade secondary to Cetuximab or Panitumumab and the SNP profile of the Epidermal Growth Factor Receptor (EGFR) domain III region.
Secondary Objectives:
Correlation of SNP profile with indicators of tumour response parameters, such as radiological response, duration of response, time to progression (TTP), overall survival (OS) time, incidence of non-dermatological adverse events.
| 2135070 | ecrin-mdr-crc