A cautionary note on using Mendelian randomization to examine the Barker hypothesis and Developmental Origins of Health and Disease (DOHaD)

2020 ◽  
pp. 1-6
Author(s):  
Shannon D’Urso ◽  
Geng Wang ◽  
Liang-Dar Hwang ◽  
Gunn-Helen Moen ◽  
Nicole M. Warrington ◽  
...  
Keyword(s):  
Cardiometabolic Risk ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Developmental Origins ◽  
Phenotypic Data ◽  
Barker Hypothesis ◽  
Maternal Genotype ◽  
Increased Risk ◽  
Offspring Genotype ◽  
Health And Disease

Abstract Recent studies have used Mendelian randomization (MR) to investigate the observational association between low birth weight (BW) and increased risk of cardiometabolic outcomes, specifically cardiovascular disease, glycemic traits, and type 2 diabetes (T2D), and inform on the validity of the Barker hypothesis. We used simulations to assess the validity of these previous MR studies, and to determine whether a better formulated model can be used in this context. Genetic and phenotypic data were simulated under a model of no direct causal effect of offspring BW on cardiometabolic outcomes and no effect of maternal genotype on offspring cardiometabolic risk through intrauterine mechanisms; where the observational relationship between BW and cardiometabolic risk was driven entirely by horizontal genetic pleiotropy in the offspring (i.e. offspring genetic variants affecting both BW and cardiometabolic disease simultaneously rather than a mechanism consistent with the Barker hypothesis). We investigated the performance of four commonly used MR analysis methods (weighted allele score MR (WAS-MR), inverse variance weighted MR (IVW-MR), weighted median MR (WM-MR), and MR-Egger) and a new approach, which tests the association between maternal genotypes related to offspring BW and offspring cardiometabolic risk after conditioning on offspring genotype at the same loci. We caution against using traditional MR analyses, which do not take into account the relationship between maternal and offspring genotypes, to assess the validity of the Barker hypothesis, as results are biased in favor of a causal relationship. In contrast, we recommend the aforementioned conditional analysis framework utilizing maternal and offspring genotypes as a valid test of not only the Barker hypothesis, but also to investigate hypotheses relating to the Developmental Origins of Health and Disease more broadly.

scholarly journals Abdominal adiposity and cardiometabolic risk factors in children and adolescents: a Mendelian randomization analysis

2019 ◽  
Vol 110 (5) ◽  
pp. 1079-1087 ◽  
Author(s):  
Anna Viitasalo ◽  
Theresia M Schnurr ◽  
Niina Pitkänen ◽  
Mette Hollensted ◽  
Tenna R H Nielsen ◽  
...  
Keyword(s):  
Risk Factors ◽  
Children And Adolescents ◽  
Cardiometabolic Risk ◽  
Dietary Habits ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genetic Risk Score ◽  
Cardiometabolic Risk Factors ◽  
Abdominal Adiposity ◽  
Increased Risk

ABSTRACT Background Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear. Objective We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization. Methods We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3–17 y. Results WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10−15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = −0.007 SD/allele; 95% CI: −0.012, −0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = −0.002 SD/allele; 95% CI: −0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal. Conclusions Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

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

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.

Epigenetics and DOHaD: how translation to predictive testing will require a better public understanding

2021 ◽  
pp. 1-7
Author(s):  
Fiona Lynch ◽  
Sharon Lewis ◽  
Ivan Macciocca ◽  
Jeffrey M. Craig
Keyword(s):  
Health Professionals ◽  
Early Life ◽  
Predictive Testing ◽  
Public Understanding ◽  
Future Research ◽  
Developmental Origins ◽  
Needed Information ◽  
Genes And Environment ◽  
Increased Risk ◽  
Health And Disease

Abstract Epigenetics is likely to play a role in the mediation of the effects of genes and environment in risk for many non-communicable diseases (NCDs). The Developmental Origins of Health and Disease (DOHaD) theory presents unique opportunities regarding the possibility of early life interventions to alter the epigenetic makeup of an individual, thereby modifying their risk for a variety of NCDs. While it is important to determine how we can lower the risk of these NCDs, it is equally important to understand how the public’s knowledge and opinion of DOHaD and epigenetic concepts may influence their willingness to undertake such interventions for themselves and their children. In this review, we provide an overview of epigenetics, DOHaD, NCDs, and the links between them. We explore the issues surrounding using epigenetics to identify those at increased risk of NCDs, including the concept of predictive testing of children. We also outline what is currently understood about the public’s understanding and opinion of epigenetics, DOHaD, and their relation to NCDs. In doing so, we demonstrate that it is essential that future research explores the public’s awareness and understanding of epigenetics and epigenetic concepts. This will provide much-needed information which will prepare health professionals for the introduction of epigenetic testing into future healthcare.

scholarly journals Prenatal Developmental Origins of Future Psychopathology: Mechanisms and Pathways

2019 ◽  
Vol 15 (1) ◽  
pp. 317-344 ◽  
Author(s):  
Catherine Monk ◽  
Claudia Lugo-Candelas ◽  
Caroline Trumpff
Keyword(s):  
Maternal Distress ◽  
Developmental Origins ◽  
Neurodevelopmental Outcomes ◽  
Fetal Origins ◽  
Behavior Development ◽  
Increased Risk ◽  
Health And Disease ◽  
Brain And Behavior ◽  
And Behavior ◽  
The Impact

The developmental origins of health and disease hypothesis applied to neurodevelopmental outcomes asserts that the fetal origins of future development are relevant to mental health. There is a third pathway for the familial inheritance of risk for psychiatric illness beyond shared genes and the quality of parental care: the impact of pregnant women's distress—defined broadly to include perceived stress, life events, depression, and anxiety—on fetal and infant brain–behavior development. We discuss epidemiological and observational clinical data demonstrating that maternal distress is associated with children's increased risk for psychopathology: For example, high maternal anxiety is associated with a twofold increase in the risk of probable mental disorder in children. We review several biological systems hypothesized to be mechanisms by which maternal distress affects fetal and child brain and behavior development, as well as the clinical implications of studies of the developmental origins of health and disease that focus on maternal distress. Development and parenting begin before birth.

scholarly journals Fetal Origins of Mental Disorders? An Answer Based on Mendelian Randomization

2018 ◽  
Vol 21 (6) ◽  
pp. 485-494 ◽  
Author(s):  
Subhi Arafat ◽  
Camelia C. Minică
Keyword(s):  
Mental Disorders ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Current Evidence ◽  
Genome Wide Association Studies ◽  
Fetal Origins ◽  
Barker Hypothesis ◽  
Main Criticism

The Barker hypothesis states that low birth weight (BW) is associated with higher risk of adult onset diseases, including mental disorders like schizophrenia, major depressive disorder (MDD), and attention deficit hyperactivity disorder (ADHD). The main criticism of this hypothesis is that evidence for it comes from observational studies. Specifically, observational evidence does not suffice for inferring causality, because the associations might reflect the effects of confounders. Mendelian randomization (MR) — a novel method that tests causality on the basis of genetic data — creates the unprecedented opportunity to probe the causality in the association between BW and mental disorders in observation studies. We used MR and summary statistics from recent large genome-wide association studies to test whether the association between BW and MDD, schizophrenia and ADHD is causal. We employed the inverse variance weighted (IVW) method in conjunction with several other approaches that are robust to possible assumption violations. MR-Egger was used to rule out horizontal pleiotropy. IVW showed that the association between BW and MDD, schizophrenia and ADHD is not causal (all p > .05). The results of all the other MR methods were similar and highly consistent. MR-Egger provided no evidence for pleiotropic effects biasing the estimates of the effects of BW on MDD (intercept = -0.004, SE = 0.005, p = .372), schizophrenia (intercept = 0.003, SE = 0.01, p = .769), or ADHD (intercept = 0.009, SE = 0.01, p = .357). Based on the current evidence, we refute the Barker hypothesis concerning the fetal origins of adult mental disorders. The discrepancy between our results and the results from observational studies may be explained by the effects of confounders in the observational studies, or by the existence of a small causal effect not detected in our study due to weak instruments. Our power analyses suggested that the upper bound for a potential causal effect of BW on mental disorders would likely not exceed an odds ratio of 1.2.

scholarly journals Association of 25-hydroxyvitamin D with cardiometabolic risk factors and metabolic syndrome: a mendelian randomization study

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Chi Chen ◽  
Yi Chen ◽  
Pan Weng ◽  
Fangzhen Xia ◽  
Qin Li ◽  
...  
Keyword(s):  
Risk Factors ◽  
Metabolic Syndrome ◽  
Vitamin D ◽  
Cardiometabolic Risk ◽  
Mendelian Randomization ◽  
Cardiometabolic Risk Factors ◽  
Metabolic Traits ◽  
Increased Risk ◽  
Vitamin D Levels ◽  
Genetically Determined

Abstract Background Low circulating vitamin D levels have been associated with increased risk of metabolic syndrome (MS) and cardiometabolic risk factors in multiple epidemiology studies. However, whether this association is causal is still unclear. We aimed to test whether genetically lowered vitamin D levels were associated with MS and its metabolic traits, using mendelian randomization (MR) methodology. Methods Ten thousand six hundred fifty-five participants were enrolled from the SPECT-China study, which was performed in 23 sites in East China during 2014 to 2016. Using four single-nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH) D concentrations, we created a genetic risk score (GRS) as instrumental variable (IV) to estimate the effect of genetically lowered 25(OH) D on MS and cardiometabolic risk factors. MS was defined according to the International Diabetes Federation criteria. Results Lower measured 25(OH)D levels were associated with MS (OR 0.921, 95% CI 0.888, 0.954) after multivariable adjustment. However, the MR-derived odds ratio of genetically determined 25(OH) D for risk of MS was 0.977 (95% CI 0.966, 1.030). The MR-derived estimates for raised fasting plasma glucose was 0.578 (95% CI 0.321, 0.980) per 10 nmol/L GRSsynthesis determined increase of 25(OH) D levels. Conclusions We found no evidence that genetically determined reduction in 25(OH)D conferred an increased risk of MS and its metabolic traits. However, we created our GRS only on the basis of common variants, which represent limited amount of variance in 25(OH)D. MR studies using rare variants, and large-scale well-designed RCTs about the effect of vitamin D supplementation on MS are warranted to further validate the findings.

scholarly journals Sex Differences in the Developmental Origins of Cardiovascular Disease

Physiology ◽  
2014 ◽  
Vol 29 (2) ◽  
pp. 122-132 ◽  
Author(s):  
Suttira Intapad ◽  
Norma B. Ojeda ◽  
John Henry Dasinger ◽  
Barbara T. Alexander
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Sex Differences ◽  
Cardiovascular Risk ◽  
Early Life ◽  
Experimental Models ◽  
Developmental Origins ◽  
Proof Of Concept ◽  
Increased Risk ◽  
Health And Disease

The Developmental Origins of Health and Disease (DOHaD) proposes that adverse events during early life program an increased risk for cardiovascular disease. Experimental models provide proof of concept but also indicate that insults during early life program sex differences in adult blood pressure and cardiovascular risk. This review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease.

scholarly journals Smoking and COVID-19: A two-sample Mendelian randomization study

2021 ◽  
Author(s):  
Bing-Kun Zheng ◽  
Na Li
Keyword(s):  
Observational Studies ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Dose Effect ◽  
Genetic Studies ◽  
Host Genetics ◽  
Causal Risk Factor ◽  
Increased Risk ◽  
Summary Data ◽  
Randomization Method

AbstractEvidence from observational studies suggested that smokers are at increased risk of coronavirus disease 2019 (COVID-19). We aimed to assess the causal effect of smoking on risk for COVID-19 susceptibility and severity using two-sample Mendelian randomization method. Smoking-associated variants were selected as instrument variables from two largest genetic studies. The latest summary data of COVID-19 that shared on Jan 18, 2021 by the COVID-19 Host Genetics Initiative was used. The present Mendelian randomization study provided genetic evidence that smoking was a causal risk factor for COVID-19 susceptibility and severity. In addition, there may be a dose-effect relationship between smoking and COVID-19 severity.

scholarly journals Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009525
Author(s):  
Mark Gormley ◽  
James Yarmolinsky ◽  
Tom Dudding ◽  
Kimberley Burrows ◽  
Richard M. Martin ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Uk Biobank ◽  
Limited Evidence ◽  
Cholesterol Lowering ◽  
Increased Risk ◽  
Secondary Analyses

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

scholarly journals Smoking is significantly associated with increased risk of COVID-19 and other respiratory infections

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Daniel B. Rosoff ◽  
Joyce Yoo ◽  
Falk W. Lohoff
Keyword(s):  
Substance Use ◽  
Observational Studies ◽  
Respiratory Diseases ◽  
Cardiometabolic Risk ◽  
Mendelian Randomization ◽  
Respiratory Infections ◽  
European Ancestry ◽  
Cardiometabolic Diseases ◽  
Increased Risk ◽  
Impact Risk

AbstractObservational studies suggest smoking, cannabis use, alcohol consumption, and substance use disorders (SUDs) may impact risk for respiratory infections, including coronavirus 2019 (COVID-2019). However, causal inference is challenging due to comorbid substance use. Using summary-level European ancestry data (>1.7 million participants), we performed single-variable and multivariable Mendelian randomization (MR) to evaluate relationships between substance use behaviors, COVID-19 and other respiratory infections. Genetic liability for smoking demonstrated the strongest associations with COVID-19 infection risk, including the risk for very severe respiratory confirmed COVID-19 (odds ratio (OR) = 2.69, 95% CI, 1.42, 5.10, P-value = 0.002), and COVID-19 infections requiring hospitalization (OR = 3.49, 95% CI, 2.23, 5.44, P-value = 3.74 × 10−8); these associations generally remained robust in models accounting for other substance use and cardiometabolic risk factors. Smoking was also strongly associated with increased risk of other respiratory infections, including asthma-related pneumonia/sepsis (OR = 3.64, 95% CI, 2.16, 6.11, P-value = 1.07 × 10−6), chronic lower respiratory diseases (OR = 2.29, 95% CI, 1.80, 2.91, P-value = 1.69 × 10−11), and bacterial pneumonia (OR = 2.14, 95% CI, 1.42, 3.24, P-value = 2.84 × 10−4). We provide strong genetic evidence showing smoking increases the risk for COVID-19 and other respiratory infections even after accounting for other substance use behaviors and cardiometabolic diseases, which suggests that prevention programs aimed at reducing smoking may be important for the COVID-19 pandemic and have substantial public health benefits.

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