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Using genetic instruments to estimate interactions in Mendelian Randomization studies

By Teri-Louise North, Neil M Davies, Sean Harrison, Alice R Carter, Gibran Hemani, Eleanor Sanderson, Kate Tilling, Laura D Howe

Posted 08 Feb 2019
bioRxiv DOI: 10.1101/544734 (published DOI: 10.1097/EDE.0000000000001096)

BACKGROUND: The interactive effect of two exposures on an outcome can be confounded. We demonstrate the use of Mendelian Randomization (MR) to estimate unconfounded additive interactions. METHODS: Using simulation, we test an extension to multivariable MR using two-stage least squares to estimate the additive interaction between two continuous exposures on a continuous outcome, including scenarios where one exposure has a causal effect on the other (mediation). The interaction parameters were set to be one third of the main effect parameters to impose a limit on the variance explained by interaction terms. We compare the performance of the two-stage least squares estimator to a Factorial MR design, in which genetic risk scores for each exposure are dichotomised to create four groups, akin to a factorial randomized controlled trial. As an illustrative example, we apply factorial MR and the 2SLS estimator to the interactive effect of education and BMI on systolic blood pressure in UK Biobank. RESULTS: Our simulations demonstrate that factorial MR has very low statistical power; 5-7% at N=50,000 and 8-23% at N=500,000 across the range of parameters tested. The two-stage least squares estimator had higher power to detect interactions than factorial MR and a lower type I error. For N=500,000, the two-stage least squares estimator had a power ranging from 29.7-92.9% and a type I error ranging from 4-6%. 95% Monte Carlo confidence intervals suggested that the estimator was unbiased to a reasonable degree of accuracy at this sample size. In comparison, the power at N=50,000 was 7-55%. CONCLUSIONS: A two-stage least squares estimator using genetic risk scores for each exposure is a more powerful alternative for detecting an unconfounded additive interaction of two exposures on an outcome than existing approaches that rely on dichotomising genetic risk scores, but it requires a large sample size and instruments of adequate strength.

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