Powerful genome-wide design and robust statistical inference in two-sample summary-data Mendelian randomization
Abstract
We develop an empirical partially Bayes statistical analysis approach where instruments are weighted according to their strength; thus weak instruments bring less variation to the estimator. The estimator is highly efficient with many weak genetic instruments and is robust to balanced and/or sparse pleiotropy. We apply our method to estimate the causal effect of body mass index (BMI) and major blood lipids on cardiovascular disease outcomes, and obtain substantially shorter confidence intervals (CIs). In particular, the estimated causal odds ratio of BMI on ischaemic stroke is 1.19 (95% CI: 1.07-1.32, P-value < 0.001); the estimated causal odds ratio of high-density lipoprotein cholesterol (HDL-C) on coronary artery disease (CAD) is 0.78 (95% CI: 0.73-0.84, P-value < 0.001). However, the estimated effect of HDL-C attenuates and become statistically non-significant when we only use strong instruments.
