Within-family studies for Mendelian randomization: avoiding dynastic, assortative mating, and population stratification biases [article]

Ben Brumpton, Eleanor Sanderson, Fernando Pires Hartwig, Sean Harrison, Gunnhild Aberge Vie, Yoonsu Cho, Laura Howe, Amanda Hughes, Dorret Boomsma, Alexandra Havdahl, John Hopper, Michael Neale (+18 others)
2019 bioRxiv   pre-print
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
more » ... illustrate these issues empirically using data from 62,470 siblings from the UK Biobank and Nord-Trondelag 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.
doi:10.1101/602516 fatcat:ql6let5g6bdvnfvkdydr562tgm