Asvold, B. | Search bioRxiv

bioRxiv2019

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

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-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.

genetics↗

bioRxiv2017

Cigarette smoking increases coffee consumption: findings from a Mendelian randomisation analysis

BackgroundSmokers tend to consume more coffee than non-smokers and there is evidence for a positive relationship between cigarette and coffee consumption in smokers. Cigarette smoke increases the metabolism of caffeine, so this association may represent a causal effect of smoking on caffeine intake.\n\nMethodsWe performed a Mendelian randomisation analysis in 114,029 individuals from the UK Biobank, 56,664 from the Norwegian HUNT study and 78,650 from the Copenhagen General Population Study. We used a genetic variant in the CHRNA5 nicotinic receptor (rs16969968) as a proxy for smoking heaviness. Coffee and tea consumption were self-reported. Analyses were conducted using linear regression and meta-analysed across studies.\n\nResultsEach additional cigarette per day consumed by current smokers was associated with higher coffee consumption (0.10 cups per day, 95% CI:0.03,0.17). There was weak evidence for an increase in tea consumption per additional cigarette smoked per day (0.04 cups per day, 95% CI:-0.002,0.07). There was strong evidence that each additional copy of the minor allele of rs16969968 (which increases daily cigarette consumption) in current smokers was associated with higher coffee consumption (0.15 cups per day, 95% CI:0.11,0.20), but only weak evidence for an association with tea consumption (0.04 cups per day, 95% CI:- 0.01,0.09). There was no clear evidence that rs16969968 was associated with coffee or tea consumption in never or former smokers.\n\nConclusionThese findings suggest that higher cigarette consumption causally increases coffee intake. This is consistent with faster metabolism of caffeine by smokers, but may also reflect behavioural links between smoking and coffee.

genetics↗