scholarly journals Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 109
Author(s):  
Anwar Mulugeta ◽  
Amanda Lumsden ◽  
Elina Hyppönen
Keyword(s):  
Vitamin D ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Uk Biobank ◽  
Reverse Causality ◽  
Hydroxyvitamin D ◽  
Inverse Variance ◽  
The Uk ◽  
Genetically Determined ◽  
The Relationship

The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.

scholarly journals 925Ethnic differences and determinants of vitamin D deficiency in the UK Biobank

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Joshua Sutherland ◽  
Ang Zhou ◽  
Matthew Leach ◽  
Elina Hyppönen
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Asian Population ◽  
European Ancestry ◽  
Uk Biobank ◽  
Mixed Ancestry ◽  
Black African ◽  
Hydroxyvitamin D ◽  
The Uk ◽  
Summer Time

Abstract Background While controversy remains regarding optimal vitamin D status, the public health relevance of true vitamin D deficiency is undisputed. There are few contemporary cross-ethnic studies investigating the prevalence and determinants of very low 25-hydroxyvitamin D [25(OH)D] concentrations. Methods We used data from 440,581 UK Biobank participants, of which 415,903 identified as white European, 7,880 Asian, 7,602 black African, 1,383 Chinese, and 6,473 of mixed ancestry. 25(OH)D concentrations were measured by DiaSorin Liaison XL and deficiency defined as ≤ 25 nmol/L 25(OH)D. Results The prevalence of 25(OH)D deficiency was highest among participants of Asian ancestry (57.2% in winter/spring and 50.8% in summer/autumn; followed by black African [38.47%/30.78%], mixed ancestry [36.53%/22.48%], Chinese [33.12%/20.68%] and white European [17.45%/5.90%], P < 1.0E-300). Participants with higher socioeconomic deprivation were more likely to have 25(OH)D deficiency compared to less deprived (P < 1.0E-300 for all comparisons), with the pattern being more apparent among those of white European ancestry and in summer (Pinteraction<6.4E-5 for both). In fully-adjusted analyses, regular consumption of oily fish was effective in mitigating ≤25 nmol/L 25(OH)D deficiency across all ethnicities, whilst outdoor-summer time was less effective for black Africans than white Europeans (OR: 0.89; 95% CI: 0.70, 1.12 and OR: 0.40; 95% CI: 0.38, 0.42, respectively). Conclusions Vitamin D deficiency remains an issue throughout the UK, particularly in lower socioeconomic areas and the UK Asian population, half of whom have vitamin D deficiency across seasons. Key messages The prevalence of 25(OH)D deficiency in the UK is alarming, with certain ethnic and socioeconomic groups considered particularly vulnerable.

Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

2021 ◽  
Author(s):  
Christa Meisinger ◽  
Dennis Freuer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Atopic Dermatitis ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
The Other ◽  
Uk Biobank ◽  
Inflammatory Bowel ◽  
The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

scholarly journals Causal Effect of the Triglyceride-Glucose Index and the Joint Exposure of Higher Glucose and Triglyceride With Extensive Cardio-Cerebrovascular Metabolic Outcomes in the UK Biobank: A Mendelian Randomization Study

2021 ◽  
Vol 7 ◽  
Author(s):  
Shucheng Si ◽  
Jiqing Li ◽  
Yunxia Li ◽  
Wenchao Li ◽  
Xiaolu Chen ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect ◽  
Heart Diseases ◽  
Cerebrovascular Diseases ◽  
European Ancestry ◽  
Uk Biobank ◽  
Tyg Index ◽  
Metabolic Outcomes ◽  
Meta Regression ◽  
The Uk

Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.

scholarly journals Using genetics to understand the causal influence of higher BMI on depression

2018 ◽  
Vol 48 (3) ◽  
pp. 834-848 ◽  
Author(s):  
Jessica Tyrrell ◽  
Anwar Mulugeta ◽  
Andrew R Wood ◽  
Ang Zhou ◽  
Robin N Beaumont ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Self Report ◽  
Uk Biobank ◽  
Men And Women ◽  
Statistical Confidence ◽  
The Uk ◽  
Genetically Determined

Abstract Background Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. Methods We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to ‘uncouple’ the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. Results Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. Conclusions Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

scholarly journals Irritable Bowel Syndrome and Migraine: Evidence From Mendelian Randomization Analysis in the UK Biobank

2021 ◽  
Author(s):  
Jie Chen ◽  
Xuejie Chen ◽  
Ying Xie ◽  
Yuhao Sun ◽  
Xiaoyan Wang ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Mendelian Randomization ◽  
Causal Association ◽  
Uk Biobank ◽  
Mendelian Randomization Analysis ◽  
Inverse Variance ◽  
Irritable Bowel ◽  
The Uk ◽  
And Control ◽  
Randomization Analysis

Abstract Background: IBS and Migraine are two diseases featuring high prevalence. Previous studies have suggested a relationship between Irritable Bowel Syndrome (IBS) and migraine, although the causal association remains unclear. We sought to explore the causal association between IBS and migraine, and to prove the importance of migraine prevention in IBS patients.Methods: This study used a two-sample Mendelian-randomization analysis to explore the association of IBS with migraine. Genetic association with migraine were acquired from the UK Biobank (UKB) genetic databases (cases: 1,072; controls: 360,122). We performed estimation using Inverse Variance Weighting (IVW), along with Maximum Likelihood, MR-RAPS, MR-Egger and Weighted Median for sensitivity analysis. Considering possible bias, we also conducted polymorphism, heterogeneity, and directional analysis.Results: The IVW estimation genetically predicted the causal association between IBS and migraine (OR=1.09, 95%CI 1.01 to 1.17, p=0.03). Neither statistical horizontal pleiotropy (MR Egger p=0.42; MR-PRESSO p=0.78) nor possible heterogeneity (IVW Q = 26.15, p=0.80) was found. Reverse causation was also not detected (p steiger<0.01).Conclusion: Mendelian randomization analysis supported a positive-going causal association of IBS with migraine, providing enlightenment for disease prevention and control.

scholarly journals Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Shucheng Si ◽  
Jiqing Li ◽  
Marlvin Anemey Tewara ◽  
Fuzhong Xue
Keyword(s):  
Mendelian Randomization ◽  
Neurological Diseases ◽  
Bipolar Disorders ◽  
Electrolyte Imbalance ◽  
Low Grade ◽  
Uk Biobank ◽  
Anemia Of Chronic Disease ◽  
The Uk ◽  
Genetically Determined ◽  
Low Grade Inflammation

BackgroundC-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions.MethodsWe used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks.ResultsWe found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population (P &lt; 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson’s disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the FDR corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders).ConclusionsGenetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions.

scholarly journals Associations of sleep and circadian phenotypes with COVID-19 susceptibility and hospitalization: an observational cohort study based on the UK Biobank and a two-sample Mendelian randomization study

SLEEP ◽  
2022 ◽  
Author(s):  
Zheran Liu ◽  
Yaxin Luo ◽  
Yonglin Su ◽  
Zhigong Wei ◽  
Ruidan Li ◽  
...  
Keyword(s):  
Cohort Study ◽  
Excessive Daytime Sleepiness ◽  
Daytime Sleepiness ◽  
Mendelian Randomization ◽  
Causal Link ◽  
Uk Biobank ◽  
Inverse Variance ◽  
Increased Risk ◽  
Weighted Median ◽  
The Uk

Abstract Study Objectives Sleep and circadian phenotypes are associated with several diseases. The present study aimed to investigate whether sleep and circadian phenotypes were causally linked with coronavirus disease 2019 (COVID-19)-related outcomes. Methods Habitual sleep duration, insomnia, excessive daytime sleepiness, daytime napping, and chronotype were selected as exposures. Key outcomes included positivity and hospitalization for COVID-19. In the observation cohort study, multivariable risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated. Two-sample Mendelian randomization (MR) analyses were conducted to estimate the causal effects of the significant findings in the observation analyses. Beta values and the corresponding 95% CIs were calculated and compared using the inverse variance weighting, weighted median, and MR-Egger methods. Results In the UK Biobank cohort study, both often excessive daytime sleepiness and sometimes daytime napping were associated with hospitalized COVID-19 (excessive daytime sleepiness [often vs. never]: RR=1.24, 95% CI=1.02-1.5; daytime napping [sometimes vs. never]: RR=1.12, 95% CI=1.02-1.22). In addition, sometimes daytime napping was also associated with an increased risk of COVID-19 susceptibility (sometimes vs. never: RR= 1.04, 95% CI=1.01-1.28). In the MR analyses, excessive daytime sleepiness was found to increase the risk of hospitalized COVID-19 (MR IVW method: OR = 4.53, 95% CI = 1.04-19.82), whereas little evidence supported a causal link between daytime napping and COVID-19 outcomes. Conclusions Observational and genetic evidence supports a potential causal link between excessive daytime sleepiness and an increased risk of COVID-19 hospitalization, suggesting that interventions targeting excessive daytime sleepiness symptoms might decrease severe COVID-19 rate.

scholarly journals Vitamin D supplement use and associated demographic, dietary and lifestyle factors in 8024 South Asians aged 40–69 years: analysis of the UK Biobank cohort

2018 ◽  
Vol 21 (14) ◽  
pp. 2678-2688 ◽  
Author(s):  
Andrea L Darling ◽  
David J Blackbourn ◽  
Kourosh R Ahmadi ◽  
Susan A Lanham-New
Keyword(s):  
Vitamin D ◽  
South Asians ◽  
Uk Biobank ◽  
Cross Sectional ◽  
Hydroxyvitamin D ◽  
Supplement Use ◽  
Supplement Usage ◽  
Vitamin D Supplements ◽  
The Uk ◽  
Vitamin D Supplement

AbstractObjectiveVitamin D deficiency (serum 25-hydroxyvitamin D<25 nmol/l) is extremely common in Western-dwelling South Asians but evidence regarding vitamin D supplement usage in this group is very limited. This work identifies demographic, dietary and lifestyle predictors associated with vitamin D supplement use.DesignCross-sectional analysis of baseline vitamin D supplement use data.SettingUK Biobank cohort.SubjectsIn total, 8024 South Asians (Bangladeshi, Indian, Pakistani), aged 40–69 years.ResultsTwenty-three per cent of men and 39 % of women (P<0·001) (22 % of Bangladeshis, 32 % of Indians, 25 % of Pakistanis (P<0·001)) took a vitamin-D-containing supplement. Median vitamin D intakes from diet were low at 1·0–3·0 µg/d, being highest in Bangladeshis and lowest in Indians (P<0·001). Logistic regression modelling showed that females had a higher odds of vitamin D supplement use than males (OR=2·02; 95 % CI 1·79, 2·28). A lower supplement usage was seen in younger persons (40–60 years v. >60 years: OR=0·75; 95 % CI 0·65, 0·86) and in those living outside Greater London (OR=0·53 to 0·77), with borderline trends for a lower BMI, higher oily fish intake and higher household income associated with increased odds of vitamin D supplement use.ConclusionsVitamin D supplements were not used by most South Asians and intakes from diet alone are likely to be insufficient to maintain adequate vitamin D status. Public health strategies are now urgently required to promote the use of vitamin D supplements in these specific UK South Asian subgroups.

scholarly journals Does Obesity Cause Thyroid Cancer? A Mendelian Randomization Study

2020 ◽  
Vol 105 (7) ◽  
pp. e2398-e2407
Author(s):  
Jonathan Mark Fussey ◽  
Robin N Beaumont ◽  
Andrew R Wood ◽  
Bijay Vaidya ◽  
Joel Smith ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Thyroid Cancer ◽  
Thyroid Disease ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Uk Biobank ◽  
Reverse Causality ◽  
The Uk

Abstract Background The incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer. Methods We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships. Results Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90). Conclusions Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.

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