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Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects

A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor f...

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Detalles Bibliográficos
Autores principales: Burgess, Stephen, Thompson, Simon G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325677/
https://www.ncbi.nlm.nih.gov/pubmed/25632051
http://dx.doi.org/10.1093/aje/kwu283
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author Burgess, Stephen
Thompson, Simon G.
author_facet Burgess, Stephen
Thompson, Simon G.
author_sort Burgess, Stephen
collection PubMed
description A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This “multivariable Mendelian randomization” approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.
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spelling pubmed-43256772015-03-02 Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects Burgess, Stephen Thompson, Simon G. Am J Epidemiol Practice of Epidemiology A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This “multivariable Mendelian randomization” approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Oxford University Press 2015-02-15 2015-01-27 /pmc/articles/PMC4325677/ /pubmed/25632051 http://dx.doi.org/10.1093/aje/kwu283 Text en © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Practice of Epidemiology
Burgess, Stephen
Thompson, Simon G.
Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects
title Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects
title_full Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects
title_fullStr Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects
title_full_unstemmed Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects
title_short Multivariable Mendelian Randomization: The Use of Pleiotropic Genetic Variants to Estimate Causal Effects
title_sort multivariable mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects
topic Practice of Epidemiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325677/
https://www.ncbi.nlm.nih.gov/pubmed/25632051
http://dx.doi.org/10.1093/aje/kwu283
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