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Mendelian Randomization (MR) has emerged as a powerful approach to leverage genetic instruments to infer causality between pairs of traits in observational studies. However, the results of such studies are susceptible to biases due to weak instruments as well as the confounding effects of population stratification and horizontal pleiotropy. Here, we show that family data can be leveraged to design MR tests that are provably robust to confounding from population stratification, assortative mating, and dynastic effects. We demonstrate in simulations that our approach, MR-Twin, is robust to confounding from population stratification and is not affected by weak instrument bias, while standard MR methods yield inflated false positive rates. We then conducted an exploratory analysis of MR-Twin and other MR methods applied to 121 trait pairs in the UK Biobank dataset. Our results suggest that confounding from population stratification can lead to false positives for existing MR methods, while MR-Twin is immune to this type of confounding, and that MR-Twin can help assess whether traditional approaches may be inflated due to confounding from population stratification.
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Weak‐instrument robust tests in two‐sample summary‐data Mendelian randomization
Abstract Mendelian randomization (MR) has been a popular method in genetic epidemiology to estimate the effect of an exposure on an outcome using genetic variants as instrumental variables (IV), with two‐sample summary‐data MR being the most popular. Unfortunately, instruments in MR studies are often weakly associated with the exposure, which can bias effect estimates and inflate Type I errors. In this work, we propose test statistics that are robust under weak‐instrument asymptotics by extending the Anderson–Rubin, Kleibergen, and the conditional likelihood ratio test in econometrics to two‐sample summary‐data MR. We also use the proposed Anderson–Rubin test to develop a point estimator and to detect invalid instruments. We conclude with a simulation and an empirical study and show that the proposed tests control size and have better power than existing methods with weak instruments.
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- Award ID(s):
- 1811414
- PAR ID:
- 10364351
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Biometrics
- Volume:
- 78
- Issue:
- 4
- ISSN:
- 0006-341X
- Format(s):
- Medium: X Size: p. 1699-1713
- Size(s):
- p. 1699-1713
- Sponsoring Org:
- National Science Foundation
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