Journal
GENETIC EPIDEMIOLOGY
Volume 40, Issue 4, Pages 304-314Publisher
WILEY
DOI: 10.1002/gepi.21965
Keywords
Mendelian randomization; instrumental variables; robust statistics; Egger regression; pleiotropy
Funding
- British Heart Foundation [RG/08/014/24067, RG/13/13/30194] Funding Source: researchfish
- Medical Research Council [MR/N501906/1, MC_UU_12013/1, MR/L003120/1, G0800270] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10165] Funding Source: researchfish
- British Heart Foundation [RG/08/014/24067, RG/13/13/30194] Funding Source: Medline
- Cancer Research UK Funding Source: Medline
- Medical Research Council [G0800270, MC_UU_12013/1, MC_UU_00002/7, MR/L003120/1, MR/N501906/1] Funding Source: Medline
- Wellcome Trust [100114] Funding Source: Medline
- MRC [MR/L003120/1, G0800270, MC_UU_12013/1] Funding Source: UKRI
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Developments in genome-wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse-variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite-sample Type 1 error rates than the inverse-variance weighted method, and is complementary to the recently proposed MR-Egger (Mendelian randomization-Egger) regression method. In analyses of the causal effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol on coronary artery disease risk, the inverse-variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR-Egger regression methods suggest a null effect of high-density lipoprotein cholesterol that corresponds with the experimental evidence. Both median-based and MR-Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants.
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