Vitamin D and the risk of treatment-resistant and atypical depression: A Mendelian randomization study
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ABSTRACT:
SUBMITTER: Arathimos R
PROVIDER: S-EPMC8568901 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe association between depression and prostate carcinogenesis has been reported in observational studies but the causality from depression on prostate cancer (PCa) remained unknown. We aimed to assess the causal effect of depression on PCa using the two-sample Mendelian randomization (MR) method.MethodsTwo sets of genetics instruments were used for analysis, derived from publicly available genetic summary data. One was 44 single-nucleotide polymorphisms (SNPs) robustly associated with major depressive disorder (MDD) and the other was two SNPs related with depressive status as ever depressed for a whole week. Inverse-variance weighted method, weighted median method, MR-Egger regression, MR Pleiotropy RESidual Sum, and Outlier test were used for MR analyses.ResultsNo evidence for an effect of MDD on PCa risk was found in inverse-variance weighted (OR: 1.12, 95% CI: 0.97-1.30, p = 0.135), MR-Egger (OR 0.89, 95% CI: 0.29-2.68, p = 0.833), and weighted median (OR: 1.08, 95% CI: 0.92-1.27, p = 0.350). Also, no strong evidence for an effect of depressive status on PCa incidence was found using the inverse-variance weighted method (OR 0.72, 95% CI: 0.35-1.47, p = 0.364).ConclusionsThe large MR analysis indicated that depression may not be causally associated with a risk of PCa.
| S-EPMC7724297 | biostudies-literature
Project description:While observational studies show an association between 25(OH)vitamin D concentrations and depressive symptoms, intervention studies, which examine the preventive effects of vitamin D supplementation on the development of depression, are lacking. To estimate the role of lowered 25(OH)vitamin D concentrations in the etiology of depressive disorders, we conducted a two-sample Mendelian randomization (MR) study on depression, i.e., "depressive symptoms" (DS, n = 161,460) and "broad depression" (BD, n = 113,769 cases and 208,811 controls). Six single nucleotide polymorphisms (SNPs), which were genome-wide significantly associated with 25(OH)vitamin D concentrations in 79,366 subjects from the SUNLIGHT genome-wide association study (GWAS), were used as an instrumental variable. None of the six SNPs was associated with DS or BD (all p > 0.05). MR analysis revealed no causal effects of 25(OH)vitamin D concentration, either on DS (inverse variance weighted (IVW); b = 0.025, SE = 0.038, p = 0.52) or on BD (IVW; b = 0.020, SE = 0.012, p = 0.10). Sensitivity analyses confirmed that 25(OH)vitamin D concentrations were not significantly associated with DS or BD. The findings from this MR study indicate no causal relationship between vitamin D concentrations and depressive symptoms, or broad depression. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.
| S-EPMC6566390 | biostudies-literature
Project description:Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.
| S-EPMC4549308 | biostudies-literature
Project description:BackgroundCirculating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe.MethodsWe used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes.ResultsThe MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99).ConclusionsThese findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.
| S-EPMC8323227 | biostudies-literature
Project description:BACKGROUND: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. METHODS: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. RESULTS: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. CONCLUSION: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.
| S-EPMC3584055 | biostudies-other
Project description:Observational studies suggest a link between depression and osteoporosis, but these may be subject to confounding and reverse causality. In this two-sample Mendelian randomization analysis, we included the large meta-analysis of genome-wide association studies for depression among 807,553 individuals (246,363 cases and 561,190 controls) of European descent, the large meta-analysis to identify genetic variants associated with femoral neck bone mineral density (FN-BMD), forearm BMD (FA-BMD) and lumbar spine BMD (LS-BMD) among 53,236 individuals of European ancestry, and the GWAS summary data of heel BMD (HE-BMD) and fracture among 426,824 individuals of European ancestry. The results revealed that genetic predisposition towards depression showed no causal effect on FA-BMD (beta-estimate: 0.091, 95% confidence interval [CI] - 0.088 to 0.269, SE:0.091, P value = 0.320), FN-BMD (beta-estimate: 0.066, 95% CI - 0.016 to 0.148, SE:0.042, P value = 0.113), LS-BMD (beta-estimate: 0.074, 95% CI - 0.029 to 0.177, SE:0.052, P value = 0.159), HE-BMD (beta-estimate: 0.009, 95% CI - 0.043 to 0.061, SE:0.027, P value = 0.727), or fracture (beta-estimate: 0.008, 95% CI - 0.071 to 0.087, SE:0.041, P value = 0.844). These results were also confirmed by multiple sensitivity analyses. Contrary to the findings of observational studies, our results do not reveal a causal role of depression in osteoporosis or fracture.
| S-EPMC8531056 | biostudies-literature
Project description:Studies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23, p = 0.004), 0.77 (SE = 0.37, p = 0.036), and 1.11 (SE = 0.39, p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings.
| S-EPMC7862438 | biostudies-literature
Project description:BackgroundVitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR).Methods and findingsFor our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D-insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations.ConclusionsOur findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.
| S-EPMC7906317 | biostudies-literature
Project description:BACKGROUND:In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS:We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS:The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20?nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS:Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.
| S-EPMC5100621 | biostudies-literature
Project description:BackgroundMore and more evidence suggests a close association between depression and hepatobiliary diseases, but its causal relationship is not yet clear.MethodUsing genome-wide association studies (GWAS) to summarize data, independent genetic variations associated with depression were selected as instrumental variables. Firstly, we designed a univariate Mendelian randomization (UVMR) analysis with two samples and simultaneously conducted reverse validation to evaluate the potential bidirectional causal relationship between depression and various hepatobiliary diseases. Secondly, we conducted a multivariate Mendelian randomization (MVMR) analysis on diseases closely related to depression, exploring the mediating effects of waist to hip ratio, hypertension, and daytime nap. The mediating effects were obtained through MVMR. For UVMR and MVMR, inverse variance weighted method (IVW) is considered the most important analytical method. Sensitivity analysis was conducted using Cochran'Q, MR Egger, and Leave-one-out methods.ResultsUVMR analysis showed that depression may increase the risk of non-alcoholic fatty liver disease (OR, 1.22; 95% CI, 1.03-1.46; p=0.0248) in liver diseases, while depression does not increase the risk of other liver diseases; In biliary and pancreatic related diseases, depression may increase the risk of cholelithiasis (OR, 1.26; 95% CI, 1.05-1.50; p=0.0120), chronic pancreatitis (OR, 1.61; 95% CI, 1.10-2.35; p=0.0140), and cholecystitis (OR, 1.23; 95% CI, 1.03-1.48; p=0.0250). In addition, through reverse validation, we found that non-alcoholic fatty liver disease, cholelithiasis, chronic pancreatitis, cholecystitis, or the inability to increase the risk of depression (p>0.05). The waist to hip ratio, hypertension, and daytime nap play a certain role in the process of depression leading to non-alcoholic fatty liver disease, with a mediating effect of 35.8%.ConclusionDepression is a susceptibility factor for non-alcoholic fatty liver disease, and the causal effect of genetic susceptibility to depression on non-alcoholic fatty liver disease is mediated by waist-hip ratio, hypertension, and daytime nap.
| S-EPMC11002219 | biostudies-literature