scholarly journals Morning diurnal preference and food intake: a Mendelian randomization study

2020 ◽  
Vol 112 (5) ◽  
pp. 1348-1357
Author(s):  
Hassan S Dashti ◽  
Angela Chen ◽  
Iyas Daghlas ◽  
Richa Saxena
Keyword(s):  
Food Intake ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Performance Outcomes ◽  
Fresh Fruit ◽  
Causal Effects ◽  
Processed Meat ◽  
Genetic Liability ◽  
Food Items ◽  
Diurnal Preference

ABSTRACT Background Poor dietary choices may underlie known associations between having an evening diurnal preference and cardiometabolic diseases. Assessing causal links between diurnal preference and food intake is now possible in Mendelian randomization (MR) analyses. Objectives We aimed to use a 2-sample MR to determine potential causal effects of genetic liability to a morning preference on food intake. We also examined potential causal effects of a morning preference on objectively captured response performances to email-administered 24-h diet recalls. Methods We used genetic variants associated with a morning preference from a published genome-wide association meta-analysis. Our outcomes included 61 food items with estimates from a food-frequency questionnaire in the UK Biobank (n = 361,194). For significant findings, we repeated the analysis using intake estimates from modified 24-h diet recalls in a subset of overlapping participants (n = 146,086). In addition, we examined 7 response performance outcomes, including the time and duration of responses to 24-h diet recalls (n = 123,035). MR effects were estimated using an inverse-variance weighted analysis. Results Genetic liability to a morning preference was associated with increased intake of 6 food items (fresh fruit, alcohol with meals, bran cereal, cereals, dried fruit, and water), decreased intake of 4 food items (beer plus cider, processed meat, other cereals [e.g., corn or frosted flakes], and full cream milk), increased temperature of hot drinks, and decreased variation in diet (PFalse Discovery Rate < 0.05). There was no evidence for an effect on coffee or tea intake. Findings for fresh fruit, beer plus cider, bran cereal, and cereal were consistent when intakes were estimated by 24-h diet recalls (P < 0.05). We also identified potential causal links between a morning preference with earlier timing and a shorter duration for completing email-administered 24-h diet recalls. Conclusions Our findings provide evidence for a potentially causal effect of a morning preference with the increased intake of foods known to constitute a healthy diet, suggesting possible health benefits of adopting a more morning diurnal preference.

scholarly journals Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer’s disease

2020 ◽  
Author(s):  
Panagiota Pagoni ◽  
Christina Dardani ◽  
Beate Leppert ◽  
Roxanna Korologou-Linden ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Educational Attainment ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Autism Spectrum ◽  
Causal Effects ◽  
Direct Effects ◽  
Limited Evidence ◽  
Genetic Liability

ABSTRACTBackgroundThere are very few studies investigating possible links between Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Alzheimer’s disease and these have been limited by small sample sizes, diagnostic and recall bias. However, neurocognitive deficits affecting educational attainment in individuals with ADHD could be risk factors for Alzheimer’s later in life while hyper plasticity of the brain in ASD and strong positive genetic correlations of ASD with IQ and educational attainment could be protective against Alzheimer’s.MethodsWe estimated the bidirectional total causal effects of genetic liability to ADHD and ASD on Alzheimer’s disease through two-sample Mendelian randomization. We investigated their direct effects, independent of educational attainment and IQ, through Multivariable Mendelian randomization.ResultsThere was limited evidence to suggest that genetic liability to ADHD (OR=1.00, 95% CI: 0.98 to 1.02, p=0.39) or ASD (OR=0.99, 95% CI: 0.97 to 1.01, p=0.70) was associated with risk of Alzheimer’s disease. Similar causal effect estimates were identified when the direct effects, independent of educational attainment (ADHD: OR=1.00, 95% CI: 0.99 to 1.01, p=0.07; ASD: OR=0.99, 95% CI: 0.98 to 1.00, p=0.28) and IQ (ADHD: OR=1.00, 95% CI: 0.99 to 1.02. p=0.29; ASD: OR=0.99, 95% CI: 0.98 to 1.01, p=0.99), were assessed. Finally, genetic liability to Alzheimer’s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR=1.12, 95% CI: 0.86 to 1.44, p=0.37; ASD: OR=1.19, 95% CI: 0.94 to 1.51, p=0.14).ConclusionsIn the first study to date investigating the causal associations between genetic liability to ADHD, ASD and Alzheimer’s, within an MR framework, we found limited evidence to suggest a causal effect. It is important to encourage future research using ADHD and ASD specific subtype data, as well as longitudinal data in order to further elucidate any associations between these conditions.

scholarly journals Genetic liability to rheumatoid arthritis on autism and autistic traits: polygenic risk score and Mendelian randomization analyses

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Amanda Ly ◽  
Beate Leppert ◽  
Dheeraj Rai ◽  
Hannah Jones ◽  
Christina Dardani ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Autistic Traits ◽  
Causal Effects ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genetic Liability ◽  
Polygenic Risk ◽  
Genome Wide

AbstractHigher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring’s own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73–1.07, p = 0.21; offspring’s own PRS on autism: RR 1.11, 95%CI 0.88–1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98–1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism.

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis

2021 ◽  
pp. 135245852199307
Author(s):  
Adil Harroud ◽  
Ruth Ann Marrie ◽  
Kathryn C Fitzgerald ◽  
Amber Salter ◽  
Yi Lu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Causal Association ◽  
Major Depressive ◽  
Genetic Liability ◽  
Bidirectional Relationship ◽  
Genetic Instruments

Background: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. Objective: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). Methods: We selected genetic instruments associated with risk of MDD ( n = 660,937 cases; 1,453,489 controls) and MS ( n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. Results: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90–1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99–1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09–1.65) and MDD (OR = 1.08, 95% CI = 1.01–1.15). Conclusion: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

scholarly journals Understanding the nature of association between anxiety phenotypes and anorexia nervosa: a triangulation approach

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
E. Caitlin Lloyd ◽  
Hannah M. Sallis ◽  
Bas Verplanken ◽  
Anne M. Haase ◽  
Marcus R. Munafò
Keyword(s):  
Anorexia Nervosa ◽  
Longitudinal Study ◽  
Anxiety Disorder ◽  
Anxiety Disorders ◽  
Causal Effect ◽  
Causal Effects ◽  
Observational Research ◽  
Genome Wide Association Studies ◽  
Genetic Liability ◽  
Depressed Affect

Abstract Background Evidence from observational studies suggests an association between anxiety disorders and anorexia nervosa (AN), but causal inference is complicated by the potential for confounding in these studies. We triangulate evidence across a longitudinal study and a Mendelian randomization (MR) study, to evaluate whether there is support for anxiety disorder phenotypes exerting a causal effect on AN risk. Methods Study One assessed longitudinal associations of childhood worry and anxiety disorders with lifetime AN in the Avon Longitudinal Study of Parents and Children cohort. Study Two used two-sample MR to evaluate: causal effects of worry, and genetic liability to anxiety disorders, on AN risk; causal effects of genetic liability to AN on anxiety outcomes; and the causal influence of worry on anxiety disorder development. The independence of effects of worry, relative to depressed affect, on AN and anxiety disorder outcomes, was explored using multivariable MR. Analyses were completed using summary statistics from recent genome-wide association studies. Results Study One did not support an association between worry and subsequent AN, but there was strong evidence for anxiety disorders predicting increased risk of AN. Study Two outcomes supported worry causally increasing AN risk, but did not support a causal effect of anxiety disorders on AN development, or of AN on anxiety disorders/worry. Findings also indicated that worry causally influences anxiety disorder development. Multivariable analysis estimates suggested the influence of worry on both AN and anxiety disorders was independent of depressed affect. Conclusions Overall our results provide mixed evidence regarding the causal role of anxiety exposures in AN aetiology. The inconsistency between outcomes of Studies One and Two may be explained by limitations surrounding worry assessment in Study One, confounding of the anxiety disorder and AN association in observational research, and low power in MR analyses probing causal effects of genetic liability to anxiety disorders. The evidence for worry acting as a causal risk factor for anxiety disorders and AN supports targeting worry for prevention of both outcomes. Further research should clarify how a tendency to worry translates into AN risk, and whether anxiety disorder pathology exerts any causal effect on AN.

scholarly journals Causal Effect Between Total Cholesterol and HDL Cholesterol as Risk Factors for Chronic Kidney Disease: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Liu Miao ◽  
Yan Min ◽  
Chuan-Meng Zhu ◽  
Jian-Hong Chen ◽  
Bin Qi ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Hdl Cholesterol ◽  
Causal Effects ◽  
Lipid Levels ◽  
Serum Lipid Levels ◽  
Genome Wide ◽  
Mr Study

Abstract Background/Aims: While observational studies show an association between serum lipid levels and cardiovascular disease (CVD), intervention studies that examine the preventive effects of serum lipid levels on the development of CKD are lacking. Methods: To estimate the role of serum lipid levels in the etiology of CKD, we conducted a two-sample Mendelian randomization (MR) study on serum lipid levels. Single nucleotide polymorphisms (SNPs), which were significantly associated genome-wide with plasma serum lipid levels from the GLGC and CKDGen consortium genome-wide association study (GWAS), including total cholesterol (TC, n = 187365), triglyceride (TG, n = 177861), HDL cholesterol (HDL-C, n = 187167), LDL cholesterol (LDL-C, n = 173082), apolipoprotein A1 (ApoA1, n = 20687), apolipoprotein B (ApoB, n = 20690) and CKD (n = 117165), were used as instrumental variables. None of the lipid-related SNPs was associated with CKD (all P > 0.05). Results: MR analysis genetically predicted the causal effect between TC/HDL-C and CKD. The odds ratio (OR) and 95% confidence interval (CI) of TC within CKD was 0.756 (0.579 to 0.933) (P = 0.002), and HDL-C was 0.85 (0.687 to 1.012) (P = 0.049). No causal effects between TG, LDL-C- ApoA1, ApoB and CKD were observed. Sensitivity analyses confirmed that TC and HDL-C were significantly associated with CKD. Conclusions: The findings from this MR study indicate causal effects between TC, HDL-C and CKD. Decreased TC and elevated HDL-C may reduce the incidence of CKD but need to be further confirmed by using a genetic and environmental approach.

scholarly journals Education, intelligence and Alzheimer’s disease: Evidence from a multivariable two-sample Mendelian randomization study

2018 ◽  
Author(s):  
Emma L Anderson ◽  
Laura D Howe ◽  
Kaitlin H Wade ◽  
Yoav Ben-Shlomo ◽  
W. David Hill ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Educational Attainment ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Univariate Analysis ◽  
Causal Effects ◽  
Training Interventions ◽  
Bidirectional Relationship ◽  
Years Of Schooling

AbstractObjectivesTo examine whether educational attainment and intelligence have causal effects on risk of Alzheimer’s disease (AD), independently of each other.DesignTwo-sample univariable and multivariable Mendelian Randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on risk of AD.Participants17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP) consortiumMain outcome measureOdds ratio of AD per standardised deviation increase in years of schooling and intelligenceResultsThere was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23% to 49%) and 35% (95% CI: 25% to 43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account, but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis.ConclusionsThere is robust evidence for an independent, causal effect of intelligence in lowering AD risk, potentially supporting a role for cognitive training interventions to improve aspects of intelligence. However, given the observed causal effect of educational attainment on intelligence, there may also be support for policies aimed at increasing length of schooling to lower incidence of AD.

Circulating adiponectin levels and systemic lupus erythematosus: a two-sample Mendelian randomization study

Rheumatology ◽  
2020 ◽  
Author(s):  
Yi-Lin Dan ◽  
Peng Wang ◽  
Zhongle Cheng ◽  
Qian Wu ◽  
Xue-Rong Wang ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Effects ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inverse Variance ◽  
Weighted Median

Abstract Objectives Several studies have reported increased serum/plasma adiponectin levels in SLE patients. This study was performed to estimate the causal effects of circulating adiponectin levels on SLE. Methods We selected nine independent single-nucleotide polymorphisms that were associated with circulating adiponectin levels (P < 5 × 10−8) as instrumental variables from a published genome-wide association study (GWAS) meta-analysis. The corresponding effects between instrumental variables and outcome (SLE) were obtained from an SLE GWAS analysis, including 7219 cases with 15 991 controls of European ancestry. Two-sample Mendelian randomization (MR) analyses with inverse-variance weighted, MR-Egger regression, weighted median and weight mode methods were used to evaluate the causal effects. Results The results of inverse-variance weighted methods showed no significantly causal associations of genetically predicted circulating adiponectin levels and the risk for SLE, with an odds ratio (OR) of 1.38 (95% CI 0.91, 1.35; P = 0.130). MR-Egger [OR 1.62 (95% CI 0.85, 1.54), P = 0.195], weighted median [OR 1.37 (95% CI 0.82, 1.35), P = 0.235) and weighted mode methods [OR 1.39 (95% CI 0.86, 1.38), P = 0.219] also supported no significant associations of circulating adiponectin levels and the risk for SLE. Furthermore, MR analyses in using SLE-associated single-nucleotide polymorphisms as an instrumental variable showed no associations of genetically predicted risk of SLE with circulating adiponectin levels. Conclusion Our study did not find evidence for a causal relationship between circulating adiponectin levels and the risk of SLE or of a causal effect of SLE on circulating adiponectin levels.

scholarly journals Interpretation of mendelian randomization using one measure of an exposure that varies over time.

2021 ◽  
Author(s):  
Tim T Morris ◽  
Jon Heron ◽  
Eleanor Sanderson ◽  
George Davey Smith ◽  
Kate Tilling
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Observational Data ◽  
Genetic Variant ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Effects ◽  
Time Points ◽  
The Life Course ◽  
Over Time

Background Mendelian randomization (MR) is a powerful tool through which the causal effects of modifiable exposures on outcomes can be estimated from observational data. Most exposures vary throughout the life course, but MR is commonly applied to one measurement of an exposure (e.g., weight measured once between ages 40 and 60). It has been argued that MR provides biased causal effect estimates when applied to one measure of an exposure that varies over time. Methods We propose an approach that emphasises the liability that causes the entire exposure trajectory. We demonstrate this approach using simulations and an applied example. Results We show that rather than estimating the direct or total causal effect of changing the exposure value at a given time, MR estimates the causal effect of changing the liability as induced by a specific genotype that gives rise to the exposure at that time. As such, results from MR conducted at different time points are expected to differ (unless the liability of exposure is constant over time), as we demonstrate by estimating the effect of BMI measured at different ages on systolic blood pressure. Conclusions Practitioners should not interpret MR results as timepoint-specific direct or total causal effects, but as the effect of changing the liability that causes the entire exposure trajectory. Estimates of how the effects of a genetic variant on an exposure vary over time are needed to interpret timepoint-specific causal effects.

scholarly journals Instrumental Heterogeneity in Sex-Specific Two-Sample Mendelian Randomization: Empirical Results From the Relationship Between Anthropometric Traits and Breast/Prostate Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yixin Gao ◽  
Jinhui Zhang ◽  
Huashuo Zhao ◽  
Fengjun Guan ◽  
Ping Zeng
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Correlation Coefficients ◽  
Causal Effects ◽  
Mr Studies ◽  
Pearson’S Correlation ◽  
Pearson's Correlation ◽  
Effect Estimation

BackgroundIn two-sample Mendelian randomization (MR) studies, sex instrumental heterogeneity is an important problem needed to address carefully, which however is often overlooked and may lead to misleading causal inference.MethodsWe first employed cross-trait linkage disequilibrium score regression (LDSC), Pearson’s correlation analysis, and the Cochran’s Q test to examine sex genetic similarity and heterogeneity in instrumental variables (IVs) of exposures. Simulation was further performed to explore the influence of sex instrumental heterogeneity on causal effect estimation in sex-specific two-sample MR analyses. Furthermore, we chose breast/prostate cancer as outcome and four anthropometric traits as exposures as an illustrative example to illustrate the importance of taking sex heterogeneity of instruments into account in MR studies.ResultsThe simulation definitively demonstrated that sex-combined IVs can lead to biased causal effect estimates in sex-specific two-sample MR studies. In our real applications, both LDSC and Pearson’s correlation analyses showed high genetic correlation between sex-combined and sex-specific IVs of the four anthropometric traits, while nearly all the correlation coefficients were larger than zero but less than one. The Cochran’s Q test also displayed sex heterogeneity for some instruments. When applying sex-specific instruments, significant discrepancies in the magnitude of estimated causal effects were detected for body mass index (BMI) on breast cancer (P = 1.63E-6), for hip circumference (HIP) on breast cancer (P = 1.25E-20), and for waist circumference (WC) on prostate cancer (P = 0.007) compared with those generated with sex-combined instruments.ConclusionOur study reveals that the sex instrumental heterogeneity has non-ignorable impact on sex-specific two-sample MR studies and the causal effects of anthropometric traits on breast/prostate cancer would be biased if sex-combined IVs are incorrectly employed.

scholarly journals Education, intelligence and Alzheimer’s disease: evidence from a multivariable two-sample Mendelian randomization study

2020 ◽  
Vol 49 (4) ◽  
pp. 1163-1172 ◽  
Author(s):  
Emma L Anderson ◽  
Laura D Howe ◽  
Kaitlin H Wade ◽  
Yoav Ben-Shlomo ◽  
W David Hill ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Educational Attainment ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Univariate Analysis ◽  
Causal Effects ◽  
Bidirectional Relationship ◽  
Robust Evidence ◽  
Years Of Schooling

Abstract Objectives To examine whether educational attainment and intelligence have causal effects on risk of Alzheimer’s disease (AD), independently of each other. Design Two-sample univariable and multivariable Mendelian randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on AD risk. Participants 17 008 AD cases and 37 154 controls from the International Genomics of Alzheimer’s Project (IGAP) consortium. Main outcome measure Odds ratio (OR) of AD per standardized deviation increase in years of schooling (SD = 3.6 years) and intelligence (SD = 15 points on intelligence test). Results There was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions [OR for intelligence on education = 0.51 SD units, 95% confidence interval (CI): 0.49, 0.54; OR for education on intelligence = 0.57 SD units, 95% CI: 0.48, 0.66]. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23–49%) and 35% (95% CI: 25–43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account (OR = 1.15, 95% CI: 0.68–1.93), but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis (OR = 0.69, 95% CI: 0.44–0.88). Conclusions There is robust evidence for an independent, causal effect of intelligence in lowering AD risk. The causal effect of educational attainment on AD risk is likely to be mediated by intelligence.

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