Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians.
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ABSTRACT:
SUBMITTER: Davies NM
PROVIDER: S-EPMC6041728 | biostudies-other | 2018
REPOSITORIES: biostudies-other
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Project description:Understanding the causal role of biomarkers in cardiovascular and other diseases is crucial in order to find effective approaches (including pharmacological therapies) for disease treatment and prevention. Classical observational studies provide naïve estimates of the likely role of biomarkers in disease development; however, such studies are prone to bias. This has direct relevance for drug development as if drug targets track to non-causal biomarkers, this can lead to expensive failure of these drugs in phase III randomised controlled trials. In an effort to provide a more reliable indication of the likely causal role of a biomarker in the development of disease, Mendelian randomisation studies are increasingly used, and this is facilitated by the availability of large-scale genetic data. We conducted a narrative review in order to provide a description of the utility of Mendelian randomisation for clinicians engaged in cardiovascular research. We describe the rationale and provide a basic description of the methods and potential limitations of Mendelian randomisation. We give examples from the literature where Mendelian randomisation has provided pivotal information for drug discovery including predicting efficacy, informing on target-mediated adverse effects and providing potential new evidence for drug repurposing. The variety of the examples presented illustrates the importance of Mendelian randomisation in order to prioritise drug targets for cardiovascular research.
| S-EPMC5574403 | biostudies-literature
Project description:Aims/hypothesisFragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality.MethodsIn total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA1c concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses.ResultsHigher fasting and non-fasting glucose and HbA1c concentrations were associated with higher risk of any fragility fracture (p<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 [1.11, 1.79], p=0.004), with similar results for fasting glucose and HbA1c in two-sample MR analyses (ORs 1.50 [1.03, 2.18], p=0.03; and 2.79 [1.12, 6.93], p=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41), p=0.06; 1.36 (0.89, 2.09), p=0.15; and 2.47 (0.95, 6.43), p=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither.Conclusions/interpretationHyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population.
| S-EPMC10789835 | biostudies-literature
Project description:Nutritional psychiatry is a growing area of research, with several nutritional factors implicated in the cause of psychiatric ill-health. However, nutritional research is highly complex, with multiple potential factors involved, highly confounded exposures and small effect sizes for individual nutrients. This Personal View considers whether Mendelian randomisation provides a solution to these difficulties, by investigating causality in a low-risk and low-cost way. We reviewed studies using Mendelian randomisation in nutritional psychiatry, along with the potential opportunities and challenges of using this approach for investigating the causal effects of nutritional exposures. Several studies have identified nutritional exposures that are potentially causal by using Mendelian randomisation in psychiatry, offering opportunities for further mechanistic research, intervention development, and replication. The use of Mendelian randomisation as a foundation for intervention development facilitates the best use of resources in an emerging discipline in which opportunities are rich, but resources are often poor.
| S-EPMC6983323 | biostudies-literature
Project description:ObjectiveTo scope the potential for (semi)-automated triangulation of Mendelian randomisation (MR) and randomised controlled trials (RCTs) evidence since the two methods have distinct assumptions that make comparisons between their results invaluable.MethodsWe mined ClinicalTrials.Gov, PubMed and EpigraphDB databases and carried out a series of 26 manual literature comparisons among 54 MR and 77 RCT publications.ResultsWe found that only 13% of completed RCTs identified in ClinicalTrials.Gov submitted their results to the database. Similarly low coverage was revealed for Semantic Medline (SemMedDB) semantic triples derived from MR and RCT publications -36% and 12%, respectively. Among intervention types that can be mimicked by MR, only trials of pharmaceutical interventions could be automatically matched to MR results due to insufficient annotation with Medical Subject Headings ontology. A manual survey of the literature highlighted the potential for triangulation across a number of exposure/outcome pairs if these challenges can be addressed.ConclusionsWe conclude that careful triangulation of MR with RCT evidence should involve consideration of similarity of phenotypes across study designs, intervention intensity and duration, study population demography and health status, comparator group, intervention goal and quality of evidence.
| S-EPMC10533809 | biostudies-literature
Project description:Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, causal inference is undermined if genetic variants used to instrument a risk factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how the 'no horizontal pleiotropy assumption' is strengthened when proteins are the risk factors of interest. Proteins are typically the proximal effectors of biological processes encoded in the genome. Moreover, proteins are the targets of most medicines, so MR studies of drug targets are becoming a fundamental tool in drug development. To enable such studies, we introduce a mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. We illustrate key model decisions and introduce an analytical framework for maximising power and evaluating the robustness of analyses.
| S-EPMC7320010 | biostudies-literature
Project description:AimsIn observational studies, type-2 diabetes is associated with increased risk of dementia; however, the causal nature of this association remains unanswered. In an unselected nationwide study of all Danes, we wanted to test whether type-2 diabetes is associated with dementia subtypes, and to test whether potential associations are of a causal nature.MethodsIn the current study of nationwide observational registry data in all Danes above the age of 65 years (n = 784 434) combined with genetic consortia data on 213 370 individuals, we investigated the associations between type-2 diabetes and Alzheimer's disease, vascular dementia, unspecified dementia and all-cause dementia, and whether observational associations were of a causal nature by applying a two-sample Mendelian randomisation strategy. We addressed key biases inherent in Mendelian randomisation approaches.ResultsImportant confounders (age, ethnicity, size of community, region, civil status and education level) were captured on all 784 434 individuals and adjusted for in the models. Multifactorial adjusted hazard ratios were 1.13 (1.06-1.21) for Alzheimer's disease, 1.98 (1.83-2.14) for vascular dementia, 1.53 (1.48-1.59) for unspecified dementia and 1.48 (1.44-1.53) for all-cause dementia in persons with type-2 diabetes v. without. Results were similar for men and women. The two-sample Mendelian randomisation estimate for the association between the genetic instrument and Alzheimer's disease was 1.04 (0.98-1.10), consistent with sensitivity estimates, addressing pleiotropy, measurement bias and weak instrument bias.ConclusionsIn a nationwide study of all Danes above the age of 65 years, we show that type-2 diabetes is associated with major subtypes of dementia - with particularly strong associations for vascular dementia and unspecified dementia - the two types of dementia with the most obvious vascular pathologies. Although the present two-sample Mendelian randomisation approach using genetic consortia data suggests that type-2 diabetes is not a direct cause of Alzheimer's disease, we were unable to test the causal nature of type-2 diabetes for vascular dementia and unspecified dementia, because no publicly available genetic consortia data yet exist for these dementia endpoints. The causal nature of type-2 diabetes for dementia with vascular pathologies is pivotal questions to solve for future public health recommendations and therapeutic advice.
| S-EPMC7214711 | biostudies-literature
Project description:Background & aimsMRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases.MethodsFirst, we performed a genome-wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures.ResultsWe identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10-8). Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective.ConclusionThe association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at-risk individuals.Lay summaryWe estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.
| S-EPMC7372222 | biostudies-literature
Project description: Not available
| S-EPMC8546498 | biostudies-literature
Project description:OBJECTIVES:To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. DESIGN:Mendelian randomisation study. SETTING:UK Biobank and international genome-wide association study data. PARTICIPANTS:Predominantly participants of European ancestry. EXPOSURE:Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. MAIN OUTCOMES MEASURE:The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. RESULTS:Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease. CONCLUSIONS:BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.
| S-EPMC6529852 | biostudies-other
Project description:OBJECTIVE:To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer's disease. DESIGN:Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables. SETTING:International Genomics of Alzheimer's Project. PARTICIPANTS:17?008 cases of Alzheimer's disease and 37?154 controls. MAIN OUTCOME MEASURES:Odds ratio of Alzheimer's per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis. RESULTS:This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer's. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10-6) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10-5) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer's (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer's and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer's. Genetically predicted alcohol consumption, serum folate, serum vitamin B12, homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer's disease. CONCLUSION:These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer's disease.
| S-EPMC5717765 | biostudies-literature