scholarly journals Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data

2018 ◽  
Vol 19 (1) ◽  
pp. 303-327 ◽  
Author(s):  
Stephen Burgess ◽  
Christopher N. Foley ◽  
Verena Zuber
Keyword(s):  
Risk Factor ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Single Gene ◽  
Study Data ◽  
Causal Inferences ◽  
Genome Wide ◽  
Multiple Regions ◽  
Polygenic Analysis

An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious. We review the Mendelian randomization paradigm for making causal inferences using genetic variants. We consider monogenic analysis, in which genetic variants are taken from a single gene region, and polygenic analysis, which includes variants from multiple regions. We focus on answering two questions: When can Mendelian randomization be used to make reliable causal inferences, and when can it be used to make relevant causal inferences?

scholarly journals Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study

2016 ◽  
Vol 47 (5) ◽  
pp. 971-980 ◽  
Author(s):  
S. H. Gage ◽  
H. J. Jones ◽  
S. Burgess ◽  
J. Bowden ◽  
G. Davey Smith ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Positive Control ◽  
Negative Control ◽  
Study Data ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Genome Wide Data

BackgroundObservational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data.MethodWe performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10−5) and schizophrenia (p < 5 × 10−8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses.ResultsThere was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01–1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05–1.14, p = 2.64 × 10−5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99–1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, p = 0.066) analyses.ConclusionsOur results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

Genetically determined atrial fibrillation and risk of stroke: a Mendelian randomization study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Fill ◽  
A Fokina ◽  
G Klappacher
Keyword(s):  
Atrial Fibrillation ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Study Data ◽  
Genome Wide Association ◽  
Large Artery ◽  
Validation Sample ◽  
Genome Wide ◽  
Genetically Determined ◽  
Genetic Instruments

Abstract Background Based on observational evidence, atrial fibrillation is a well-established risk factor of stroke to be considered for antithrombotic treatment in presence of additional clinical conditions derived from multivariate risk models. Although biologically plausible, it however still is unknown whether this association is causal and confined to the embolic stroke subtype. Purpose Our objective was to explore whether genetically determined manifestation of atrial fibrillation was associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study on publicly available summary statistics from GWAS consortia. Methods Genetic instruments for atrial fibrillation were obtained from the AFGen Consortium comprising 17,931 cases and 115,142 controls. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance–weighted meta-analysis, weighted-median analysis, Mendelian randomization–Egger regression, and multivariable Mendelian randomization. The dataset of Nielsen et al. comprising a total of 60,620 cases with atrial fibrillation and 970,216 controls of European ancestry from six contributing studies was used as an independent validation sample. Genetic instruments for atrial fibrillation were further tested for association with etiologically related traits by using publicly available genome-wide association study data. Results Genetic predisposition to atrial fibrillation was associated with higher risk of any stroke (beta coefficient [b] ± standard error [se] = 0.22±0.04; P=0.0001), any ischemic stroke (b ± se = 0.24±0.05; P=0.0003), and cardioembolic stroke (b ± se = 0.76±0.10; P&lt;0.0001), but not with small-vessel stroke or large artery stroke, see figure. Analyses in the validation sample showed similar associations (any stroke: b ± se = 0.19±0.04; P&lt;0.0001; any ischemic stroke: b ± se = 0.21±0.04; P&lt;0.0001; cardioembolic stroke: b ± se = 0.82±0.13; P&lt;0.0001). Genetically determined atrial fibrillation was further weakly associated with chronic kidney disease (b ± se = 0.10±0.04; P=0.0261), but not with coronary artery disease and myocardial infarction or any other available phenotype. Conclusions Genetic predisposition to atrial fibrillation is associated with higher risk of any stroke, mainly driven by the ischemic and cardioembolic subtypes. In contrast, large artery and small-vessel strokes did not exhibit a causal relationship with atrial fibrillation. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Medical University of Vienna, Austria

scholarly journals A genome wide association study of frozen shoulder identifies a common variant of WNT7B and diabetes as causal risk factors

2020 ◽  
Author(s):  
Harry D Green ◽  
Alistair Jones ◽  
Jonathan P Evans ◽  
Andrew R Wood ◽  
Robin N Beaumont ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Frozen Shoulder ◽  
Biological Mechanisms ◽  
Causal Gene ◽  
Painful Condition ◽  
Causal Risk Factor ◽  
Genome Wide ◽  
A Genome

AbstractFrozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes.We performed a genome wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 2064 cases identified from ICD-10 codes. We used data from FinnGen for replication. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder.We identified a single genome-wide significant locus (lead SNP rs62228062; OR=1.34 [1.28-1.41], p=2×10−16) that contained WNT7B. A recent transcriptome study identified WNT7B as amongst the most enriched transcripts in anterior capsule tissue in patients undergoing arthroscopic capsulotomy surgery for frozen shoulder suggesting WNT7B as a potential causal gene at the locus. The lead SNP was also strongly associated with Dupuytren’s contracture (OR=2.61 [2.50, 2.72], p<1×10−100). The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR=1.04 [1.02-1.07], p=6×10−5). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects.We have identified the first genetic variant associated with frozen shoulder. WNT7B is a potential causal gene at the locus. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.

scholarly journals Association Between Environmental Factors and Asthma Using Mendelian Randomization: Increased Effect of Body Mass Index on Adult-Onset Moderate-to-Severe Asthma Subtypes

2021 ◽  
Vol 12 ◽  
Author(s):  
Tae-Woong Ha ◽  
Hae-Un Jung ◽  
Dong Jun Kim ◽  
Eun Ju Baek ◽  
Won Jun Lee ◽  
...  
Keyword(s):  
Risk Factor ◽  
Environmental Factors ◽  
Severe Asthma ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effects ◽  
Genome Wide Association ◽  
Adult Onset ◽  
Uk Biobank ◽  
Genome Wide

Although asthma is one of the most common chronic diseases throughout all age groups, its etiology remains unknown, primarily due to its heterogeneous characteristics. We examined the causal effects of various environmental factors on asthma using Mendelian randomization and determined whether the susceptibility to asthma due to the causal effect of a risk factor differs between asthma subtypes, based on age of onset, severity of asthma, and sex. We performed Mendelian randomization analyses (inverse variance weighted, weighted median, and generalized summary-data-based Mendelian randomization) using UK Biobank data to estimate the causal effects of 69 environmental factors on asthma. Additional sensitivity analyses (MR-Egger regression, Cochran’s Q test, clumping, and reverse Mendelian randomization) were performed to ensure minimal or no pleiotropy. For confirmation, two-sample setting analyses were replicated using BMI SNPs that had been reported by a meta-genome-wide association study in Japanese and European (GIANT) populations and a genome-wide association study in control individuals from the UK Biobank. We found that BMI causally affects the development of asthma and that the adult-onset moderate-to-severe asthma subtype is the most susceptible to causal inference by BMI. Further, it is likely that the female subtype is more susceptible to BMI than males among adult asthma cases. Our findings provide evidence that obesity is a considerable risk factor in asthma patients, particularly in adult-onset moderate-to-severe asthma cases, and that weight loss is beneficial for reducing the burden of asthma.

scholarly journals A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009577
Author(s):  
Harry D. Green ◽  
Alistair Jones ◽  
Jonathan P. Evans ◽  
Andrew R. Wood ◽  
Robin N. Beaumont ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Frozen Shoulder ◽  
Genome Wide Association ◽  
Biological Mechanisms ◽  
Painful Condition ◽  
Causal Risk Factor ◽  
Genome Wide ◽  
A Genome

Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40–60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16–1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren’s disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02–1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren’s disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.

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