Mendelian randomization case-control PheWAS in UK Biobank shows evidence of causality for smoking intensity in 28 distinct clinical conditions

AbstractObjectivesTo assess bidirectional effects of anxiety and anorexia nervosa (AN) phenotypes. Design Two-sample Mendelian randomization.SettingGenome-wide association study (GWAS) summary statistics from the Psychiatric Genomics Consortium (PGC), analysis of the UK Biobank sample, and Anxiety Neuro Genetics Study (ANGST) consortium.ParticipantsEuropean descent participants from the PGC (n = 14,477), UK Biobank (n = 348,219), and ANGST consortium (n = 17,310, and n = 18,186).Main outcome measuresAN diagnosis, worry, anxiety disorder pathology (case-control and quantitative phenotypes).ResultsWe found evidence of a moderate genetic correlation between worry and AN (Rg = 0.36, SE = 0.05, p < 0.001), and the Mendelian randomization analysis supported a causal influence of worry on AN (OR = 2.14, 95% CI: 1.18 to 3.90, p = 0.01). There was no clear evidence for a causal effect of AN on worry in this study (B = −0.01, 95% CI: −0.03 to 0.02, p = 0.55). There was no robust evidence for a causal influence of anxiety disorders on AN (for case-control anxiety disorder phenotype: OR = 1.02, 95% CI: 0.69, 1.50, p = 0.922; for quantitative anxiety disorder phenotype: OR = 4.26, 95% CI: 0.49, 36.69, p = 0.187). There was no robust evidence for a causal effect of AN on anxiety disorders (for case control anxiety disorder phenotype: OR = 1.00, 95% CI: 0.72, 1.38, p = 0.981; for quantitative anxiety disorder phenotype: B = 0.01, 95% CI: −0.06, 0.6=09, p = 0,761). AN and anxiety disorder phenotypes were not genetically correlated (for case-control anxiety disorder phenotype: Rg = 0.10, se = 0.17, p = .56; for quantitative anxiety disorder phenotype: Rg = 0.12, SE = 0.17, p = 0.47).ConclusionsFindings support a role for worry in AN development, highlighting a potential target of future AN prevention efforts. Mechanisms underlying the association should be a focus of future investigation. The relatively small sample sizes of anxiety disorder and AN GWASs may have limited power to detect causal effects; these associations should be studied further.

Download Full-text

Association between Depression and Multiple Disease Outcomes: A Phenome-Wide Mendelian Randomization Study in the UK Biobank

SSRN Electronic Journal ◽

10.2139/ssrn.3223944 ◽

2018 ◽

Author(s):

Anwar Mulugeta Gebremichael ◽

Ang Zhou ◽

Catherine King ◽

Elina Hyppönen

Keyword(s):

Mendelian Randomization ◽

Uk Biobank ◽

Disease Outcomes ◽

Multiple Disease Outcomes ◽

The Uk

Download Full-text

Linguistic feature of anorexia nervosa: a prospective case–control pilot study

Eating and Weight Disorders - Studies on Anorexia Bulimia and Obesity ◽

10.1007/s40519-021-01273-7 ◽

2021 ◽

Author(s):

Vittoria Cuteri ◽

Giulia Minori ◽

Gloria Gagliardi ◽

Fabio Tamburini ◽

Elisabetta Malaspina ◽

...

Keyword(s):

Anorexia Nervosa ◽

Language Processing ◽

Statistical Significance ◽

Case Control ◽

Pathological Process ◽

Linguistic Features ◽

Level Of Evidence ◽

Linguistic Feature ◽

Linguistic Markers ◽

Clinical Conditions

Abstract Purpose Attention has recently been paid to Clinical Linguistics for the detection and support of clinical conditions. Many works have been published on the “linguistic profile” of various clinical populations, but very few papers have been devoted to linguistic changes in patients with eating disorders. Patients with Anorexia Nervosa (AN) share similar psychological features such as disturbances in self-perceived body image, inflexible and obsessive thinking and anxious or depressive traits. We hypothesize that these characteristics can result in altered linguistic patterns and be detected using the Natural Language Processing tools. Methods We enrolled 51 young participants from December 2019 to February 2020 (age range: 14–18): 17 girls with a clinical diagnosis of AN, and 34 normal-weighted peers, matched by gender, age and educational level. Participants in each group were asked to produce three written texts (around 10–15 lines long). A rich set of linguistic features was extracted from the text samples and the statistical significance in pinpointing the pathological process was measured. Results Comparison between the two groups showed several linguistics indexes as statistically significant, with syntactic reduction as the most relevant trait of AN productions. In particular, the following features emerge as statistically significant in distinguishing AN girls and their normal-weighted peers: the length of the sentences, the complexity of the noun phrase, and the global syntactic complexity. This peculiar pattern of linguistic erosion may be due to the severe metabolic impairment also affecting the central nervous system in AN. Conclusion These preliminary data showed the existence of linguistic parameters as probable linguistic markers of AN. However, the analysis of a bigger cohort, still ongoing, is needed to consolidate this assumption. Level of evidence III Evidence obtained from case–control analytic studies.

Download Full-text

Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02494-4 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Maria Bruzelius ◽

Susanna C. Larsson

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

Download Full-text

Genetic predictors of participation in optional components of UK Biobank

Nature Communications ◽

10.1038/s41467-021-21073-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jessica Tyrrell ◽

Jie Zheng ◽

Robin Beaumont ◽

Kathryn Hinton ◽

Tom G. Richardson ◽

...

Keyword(s):

Sensitivity Analysis ◽

Genetic Variants ◽

Genetic Factors ◽

Mendelian Randomization ◽

Genetic Correlations ◽

Mr Studies ◽

Uk Biobank ◽

Factors Affecting ◽

Participation Bias ◽

Genetic Predictors

AbstractLarge studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation bias across different studies. 32 variants were associated with participation in one of the optional components (P < 6 × 10−9), including loci with links to intelligence and Alzheimer’s disease. Genetic correlations demonstrated that participation bias was common across studies. MR showed that longer educational duration, older menarche and taller stature increased participation, whilst higher levels of adiposity, dyslipidaemia, neuroticism, Alzheimer’s and schizophrenia reduced participation. Our effect estimates can be used for sensitivity analysis to account for selective participation biases in genetic or non-genetic analyses.

Download Full-text

Associations of observational and genetically determined caffeine intake with coronary artery disease and diabetes

European Heart Journal ◽

10.1093/ehjci/ehaa946.1493 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Said ◽

Y.J Van De Vegte ◽

N Verweij ◽

P Van Der Harst

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Mendelian Randomization ◽

Cox Regression ◽

Caffeine Intake ◽

Uk Biobank ◽

Genome Wide ◽

Artery Disease ◽

Genetically Determined

Abstract Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes (T2D). However, whether these associations are causal remains unknown. Objectives This study aimed to identify genetic variants associated with caffeine intake, and to investigate possible causal links between genetically determined caffeine intake and CAD or T2D. Additionally, we aimed to replicate previous observational findings between caffeine intake and CAD or T2D. Methods Genome wide associated studies (GWAS) were performed on caffeine intake from coffee, tea or both in 407,072 UK Biobank participants. Identified variants were used in a two-sample Mendelian randomization (MR) approach to investigate evidence for causal links between caffeine intake and CAD in CARDIoGRAMplusC4D (60,801 cases; 123,504 controls) or T2D in DIAGRAM (26,676 cases; 132,532 controls). Observational associations were tested within UK Biobank using Cox regression analyses. Results Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2D compared to no or high intake, with the lowest risks at intakes of 120–180 mg/day from coffee for CAD (HR=0.77 [95% CI: 0.73–0.82; P<1e-16]), and 300–360 mg/day for T2D (HR=0.76 [95% CI: 0.67–0.86]; P=1.57e-5). GWAS identified 51 novel genetic loci associated with caffeine intake, enriched for central nervous system genes. In contrast to observational analyses, MR analyses in CARDIoGRAMplusC4D and DIAGRAM yielded no evidence for causal links between caffeine intake and the development of CAD or T2D. Conclusions MR analyses indicate caffeine intake might not protect against CAD or T2D, despite protective associations in observational analyses. Manhattan_plot_CaffeineIntake Funding Acknowledgement Type of funding source: None

Download Full-text

Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study

npj Genomic Medicine ◽

10.1038/s41525-021-00189-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Shuai Yuan ◽

Edward L. Giovannucci ◽

Susanna C. Larsson

Keyword(s):

Type 2 Diabetes ◽

Chronic Pancreatitis ◽

Alcohol Consumption ◽

Mendelian Randomization ◽

Gallstone Disease ◽

Smoking Initiation ◽

Disease Type ◽

Uk Biobank ◽

Increased Risk

AbstractWe conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10−8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.

Download Full-text

Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study

Nutrients ◽

10.3390/nu13072218 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2218

Author(s):

Shuai Yuan ◽

Paul Carter ◽

Amy M. Mason ◽

Stephen Burgess ◽

Susanna C. Larsson

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Diseases ◽

Intracerebral Hemorrhage ◽

Genetic Variants ◽

Odds Ratio ◽

Observational Studies ◽

Mendelian Randomization ◽

Coffee Consumption ◽

Uk Biobank ◽

The Uk

Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91; 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded.

Download Full-text