Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses
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Published:2020-07-14
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Brumpton BenORCID, Sanderson EleanorORCID, Heilbron Karl, Hartwig Fernando PiresORCID, Harrison SeanORCID, Vie Gunnhild ÅbergeORCID, Cho YoonsuORCID, Howe Laura D., Hughes Amanda, Boomsma Dorret I., Havdahl AlexandraORCID, Hopper John, Neale MichaelORCID, Nivard Michel G.ORCID, Pedersen Nancy L., Reynolds Chandra A., Tucker-Drob Elliot M., Grotzinger AndrewORCID, Howe Laurence, Morris TimORCID, Li Shuai, Brumpton Ben, Sanderson Eleanor, Heilbron Karl, Hartwig Fernando Pires, Harrison Sean, Vie Gunnhild Åberge, Cho Yoonsu, Howe Laura D., Hughes Amanda, Boomsma Dorret I., Havdahl Alexandra, Hopper John, Neale Michael, Nivard Michel G., Pedersen Nancy L., Reynolds Chandra A., Tucker-Drob Elliot M., Grotzinger Andrew, Howe Laurence, Morris Tim, Li Shuai, Auton Adam, Windmeijer Frank, Chen Wei-Min, Bjørngaard Johan Håkon, Hveem Kristian, Willer Cristen, Evans David M., Kaprio Jaakko, Smith George Davey, Åsvold Bjørn Olav, Hemani Gibran, Davies Neil M., Heilbron Karl, Auton Adam, Auton Adam, Windmeijer Frank, Chen Wei-Min, Bjørngaard Johan Håkon, Hveem Kristian, Willer CristenORCID, Evans David M.ORCID, Kaprio JaakkoORCID, Davey Smith GeorgeORCID, Åsvold Bjørn Olav, Hemani GibranORCID, Davies Neil M.ORCID, ,
Abstract
AbstractEstimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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