TY - JOUR T1 - Within-family studies for Mendelian randomization: avoiding dynastic, assortative mating, and population stratification biases JF - bioRxiv DO - 10.1101/602516 SP - 602516 AU - Ben Brumpton AU - Eleanor Sanderson AU - Fernando Pires Hartwig AU - Sean Harrison AU - Gunnhild Åberge Vie AU - Yoonsu Cho AU - Laura D Howe AU - Amanda Hughes AU - Dorret I Boomsma AU - Alexandra Havdahl AU - John Hopper AU - Michael Neale AU - Michel G Nivard AU - Nancy L Pedersen AU - Chandra A Reynolds AU - Elliot M Tucker-Drob AU - Andrew Grotzinger AU - Laurence Howe AU - Tim Morris AU - Shuai Li AU - MR within-family Consortium AU - Wei-Min Chen AU - Johan Håkon Bjørngaard AU - Kristian Hveem AU - Cristen Willer AU - David M Evans AU - Jaakko Kaprio AU - Bjørn Olav Åsvol AU - George Davey Smith AU - Bjørn Olav Åsvold AU - Gibran Hemani AU - Neil M Davies Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/07/05/602516.abstract N2 - Mendelian randomization (MR) is a widely-used method for causal inference using genetic data. Mendelian randomization studies of unrelated individuals may be susceptible to bias from family structure, for example, through dynastic effects which occur when parental genotypes directly affect offspring phenotypes. Here we describe methods for within-family Mendelian randomization and through simulations show that family-based methods can overcome bias due to dynastic effects. We illustrate these issues empirically using data from 61,008 siblings from the UK Biobank and Nord-Trøndelag Health Study. Both within-family and population-based Mendelian randomization analyses reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while MR estimates from population-based samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects largely disappeared in within-family MR analyses. We found differences between population-based and within-family based estimates, indicating the importance of controlling for family effects and population structure in Mendelian randomization studies. ER -