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A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data

Mendelian randomization makes use of genetic variants as instrumental variables to eliminate the influence induced by unknown confounders on causal estimation in epidemiology studies. However, with the soaring genetic variants identified in genome-wide association studies, the pleiotropy, and linkag...

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Autores principales: Wang, Yuquan, Li, Tingting, Fu, Liwan, Yang, Siqian, Hu, Yue-Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312241/
https://www.ncbi.nlm.nih.gov/pubmed/34322150
http://dx.doi.org/10.3389/fgene.2021.634394
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author Wang, Yuquan
Li, Tingting
Fu, Liwan
Yang, Siqian
Hu, Yue-Qing
author_facet Wang, Yuquan
Li, Tingting
Fu, Liwan
Yang, Siqian
Hu, Yue-Qing
author_sort Wang, Yuquan
collection PubMed
description Mendelian randomization makes use of genetic variants as instrumental variables to eliminate the influence induced by unknown confounders on causal estimation in epidemiology studies. However, with the soaring genetic variants identified in genome-wide association studies, the pleiotropy, and linkage disequilibrium in genetic variants are unavoidable and may produce severe bias in causal inference. In this study, by modeling the pleiotropic effect as a normally distributed random effect, we propose a novel mixed-effects regression model-based method PLDMR, pleiotropy and linkage disequilibrium adaptive Mendelian randomization, which takes linkage disequilibrium into account and also corrects for the pleiotropic effect in causal effect estimation and statistical inference. We conduct voluminous simulation studies to evaluate the performance of the proposed and existing methods. Simulation results illustrate the validity and advantage of the novel method, especially in the case of linkage disequilibrium and directional pleiotropic effects, compared with other methods. In addition, by applying this novel method to the data on Atherosclerosis Risk in Communications Study, we conclude that body mass index has a significant causal effect on and thus might be a potential risk factor of systolic blood pressure. The novel method is implemented in R and the corresponding R code is provided for free download.
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spelling pubmed-83122412021-07-27 A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data Wang, Yuquan Li, Tingting Fu, Liwan Yang, Siqian Hu, Yue-Qing Front Genet Genetics Mendelian randomization makes use of genetic variants as instrumental variables to eliminate the influence induced by unknown confounders on causal estimation in epidemiology studies. However, with the soaring genetic variants identified in genome-wide association studies, the pleiotropy, and linkage disequilibrium in genetic variants are unavoidable and may produce severe bias in causal inference. In this study, by modeling the pleiotropic effect as a normally distributed random effect, we propose a novel mixed-effects regression model-based method PLDMR, pleiotropy and linkage disequilibrium adaptive Mendelian randomization, which takes linkage disequilibrium into account and also corrects for the pleiotropic effect in causal effect estimation and statistical inference. We conduct voluminous simulation studies to evaluate the performance of the proposed and existing methods. Simulation results illustrate the validity and advantage of the novel method, especially in the case of linkage disequilibrium and directional pleiotropic effects, compared with other methods. In addition, by applying this novel method to the data on Atherosclerosis Risk in Communications Study, we conclude that body mass index has a significant causal effect on and thus might be a potential risk factor of systolic blood pressure. The novel method is implemented in R and the corresponding R code is provided for free download. Frontiers Media S.A. 2021-07-12 /pmc/articles/PMC8312241/ /pubmed/34322150 http://dx.doi.org/10.3389/fgene.2021.634394 Text en Copyright © 2021 Wang, Li, Fu, Yang and Hu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Wang, Yuquan
Li, Tingting
Fu, Liwan
Yang, Siqian
Hu, Yue-Qing
A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data
title A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data
title_full A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data
title_fullStr A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data
title_full_unstemmed A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data
title_short A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data
title_sort novel method for mendelian randomization analyses with pleiotropy and linkage disequilibrium in genetic variants from individual data
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312241/
https://www.ncbi.nlm.nih.gov/pubmed/34322150
http://dx.doi.org/10.3389/fgene.2021.634394
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