Faculty Opinions recommendation of Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.

Author(s):  
Frank Harrell
2019 ◽  
Vol 28 (R2) ◽  
pp. R170-R179 ◽  
Author(s):  
Neil M Davies ◽  
Laurence J Howe ◽  
Ben Brumpton ◽  
Alexandra Havdahl ◽  
David M Evans ◽  
...  

Abstract Mendelian randomization (MR) is increasingly used to make causal inferences in a wide range of fields, from drug development to etiologic studies. Causal inference in MR is possible because of the process of genetic inheritance from parents to offspring. Specifically, at gamete formation and conception, meiosis ensures random allocation to the offspring of one allele from each parent at each locus, and these are unrelated to most of the other inherited genetic variants. To date, most MR studies have used data from unrelated individuals. These studies assume that genotypes are independent of the environment across a sample of unrelated individuals, conditional on covariates. Here we describe potential sources of bias, such as transmission ratio distortion, selection bias, population stratification, dynastic effects and assortative mating that can induce spurious or biased SNP–phenotype associations. We explain how studies of related individuals such as sibling pairs or parent–offspring trios can be used to overcome some of these sources of bias, to provide potentially more reliable evidence regarding causal processes. The increasing availability of data from related individuals in large cohort studies presents an opportunity to both overcome some of these biases and also to evaluate familial environmental effects.


2018 ◽  
Vol 19 (1) ◽  
pp. 303-327 ◽  
Author(s):  
Stephen Burgess ◽  
Christopher N. Foley ◽  
Verena Zuber

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?


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Noah Lorincz-Comi ◽  
Xiaofeng Zhu

AbstractMany cardiometabolic conditions have demonstrated associative evidence with COVID-19 hospitalization risk. However, the observational designs of the studies in which these associations are observed preclude causal inferences of hospitalization risk. Mendelian Randomization (MR) is an alternative risk estimation method more robust to these limitations that allows for causal inferences. We applied four MR methods (MRMix, IMRP, IVW, MREgger) to publicly available GWAS summary statistics from European (COVID-19 GWAS n = 2956) and multi-ethnic populations (COVID-19 GWAS n = 10,908) to better understand extant causal associations between Type II Diabetes (GWAS n = 659,316), BMI (n = 681,275), diastolic and systolic blood pressure, and pulse pressure (n = 757,601 for each) and COVID-19 hospitalization risk across populations. Although no significant causal effect evidence was observed, our data suggested a trend of increasing hospitalization risk for Type II diabetes (IMRP OR, 95% CI 1.67, 0.96–2.92) and pulse pressure (OR, 95% CI 1.27, 0.97–1.66) in the multi-ethnic sample. Type II diabetes and Pulse pressure demonstrates a potential causal association with COVID-19 hospitalization risk, the proper treatment of which may work to reduce the risk of a severe COVID-19 illness requiring hospitalization. However, GWAS of COVID-19 with large sample size is warranted to confirm the causality.


2010 ◽  
Vol 5 (6) ◽  
pp. 545-559 ◽  
Author(s):  
Weijing He ◽  
John Castiblanco ◽  
Elizabeth A Walter ◽  
Jason F Okulicz ◽  
Sunil K Ahuja

2021 ◽  
Author(s):  
Noah J Lorincz-Comi ◽  
Xiaofeng Zhu

Many cardiometabolic conditions have demonstrated associative evidence with COVID-19 hospitalization risk. However, the observational designs of the studies in which these associations are observed preclude causal inferences of hospitalization risk. Mendelian Randomization (MR) is an alternative risk estimation method more robust to these limitations that allows for causal inferences. We applied four MR methods (MRMix, IMRP, IVW, MREgger) to publicly available GWAS summary statistics from European (COVID-19 GWAS n=2,956) and multi-ethnic populations (COVID-19 GWAS n=10,808) to better understand extant causal associations between Type II Diabetes (GWAS n=659,316), BMI (n=681,275), diastolic and systolic blood pressure, and pulse pressure (n=757,601 for each) and COVID-19 hospitalization risk across populations. Although no significant causal effect evidence was observed, our data suggested a trend of increasing hospitalization risk for Type II diabetes (IMRP OR, 95% CI: 1.67, 0.96-2.92) and pulse pressure (OR, 95% CI: 1.27, 0.97-1.66) in the multi-ethnic sample. Type II diabetes and Pulse pressure demonstrates a potential causal association with COVID-19 hospitalization risk, the proper treatment of which may work to reduce the risk of a severe COVID-19 illness requiring hospitalization. However, GWAS of COVID-19 with large sample size is warranted to confirm the causality.


2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Adriaan van der Graaf ◽  
◽  
Annique Claringbould ◽  
Antoine Rimbert ◽  
Harm-Jan Westra ◽  
...  

Abstract Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.


2008 ◽  
Vol 27 (8) ◽  
pp. 1133-1163 ◽  
Author(s):  
Debbie A. Lawlor ◽  
Roger M. Harbord ◽  
Jonathan A. C. Sterne ◽  
Nic Timpson ◽  
George Davey Smith

2015 ◽  
Vol 79 (3-4) ◽  
pp. 194-204 ◽  
Author(s):  
Andreas Ziegler ◽  
Henry Mwambi ◽  
Inke R. König

2017 ◽  
Author(s):  
Venexia M Walker ◽  
George Davey Smith ◽  
Neil M Davies ◽  
Richard M Martin

ABSTRACTIdentification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current observational research methods are subject to several biases. These include confounding by indication, reverse causality, and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evidence from this method and other approaches, in the spirit of triangulation, to improve causal inferences concerning drug effects. MR overcomes some of the limitations associated with the existing methods in this field. Furthermore, it can be applied either pre- or post-approval of the drug and could therefore prevent the potentially harmful exposure of patients in clinical trials and beyond. The potential of MR as a pharmacovigilance and drug repurposing tool is yet to be realized and could both help prevent adverse drug events and identify novel indications for existing drugs in the future.


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