TY - JOUR
T1 - Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses
AU - Brumpton, Ben
AU - Sanderson, Eleanor
AU - Heilbron, Karl
AU - Hartwig, Fernando Pires
AU - Harrison, Sean
AU - Vie, Gunnhild Åberge
AU - Cho, Yoonsu
AU - Howe, Laura D.
AU - Hughes, Amanda
AU - Boomsma, Dorret I.
AU - Havdahl, Alexandra
AU - Hopper, John
AU - Neale, Michael
AU - Nivard, Michel G.
AU - Pedersen, Nancy L.
AU - Reynolds, Chandra A.
AU - Tucker-Drob, Elliot M.
AU - Grotzinger, Andrew
AU - Howe, Laurence
AU - Morris, Tim
AU - Li, Shuai
AU - Brumpton, Ben
AU - Sanderson, Eleanor
AU - Heilbron, Karl
AU - Hartwig, Fernando Pires
AU - Harrison, Sean
AU - Vie, Gunnhild Åberge
AU - Cho, Yoonsu
AU - Howe, Laura D.
AU - Hughes, Amanda
AU - Boomsma, Dorret I.
AU - Havdahl, Alexandra
AU - Hopper, John
AU - Neale, Michael
AU - Nivard, Michel G.
AU - Pedersen, Nancy L.
AU - Reynolds, Chandra A.
AU - Tucker-Drob, Elliot M.
AU - Grotzinger, Andrew
AU - Howe, Laurence
AU - Morris, Tim
AU - Li, Shuai
AU - Auton, Adam
AU - Windmeijer, Frank
AU - Chen, Wei Min
AU - Bjørngaard, Johan Håkon
AU - Hveem, Kristian
AU - Willer, Cristen
AU - Evans, David M.
AU - Kaprio, Jaakko
AU - Smith, George Davey
AU - Åsvold, Bjørn Olav
AU - Hemani, Gibran
AU - Davies, Neil M.
AU - Heilbron, Karl
AU - Auton, Adam
AU - Auton, Adam
AU - Windmeijer, Frank
AU - Chen, Wei Min
AU - Bjørngaard, Johan Håkon
AU - Hveem, Kristian
AU - Willer, Cristen
AU - Evans, David M.
AU - Kaprio, Jaakko
AU - Davey Smith, George
AU - Åsvold, Bjørn Olav
AU - Hemani, Gibran
AU - Davies, Neil M.
AU - The Within-family Consortium, Within-family Consortium
AU - The 23andMe Research Team
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Estimates 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.
AB - Estimates 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85087978841&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-17117-4
DO - 10.1038/s41467-020-17117-4
M3 - Article
C2 - 32665587
AN - SCOPUS:85087978841
VL - 11
SP - 1
EP - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3519
ER -