TEMR: Trans-ethnic mendelian randomization method using large-scale GWAS summary datasets.

Abstract

Available large-scale genome-wide association study (GWAS) summary datasets predominantly stem from European populations, while sample sizes for other ethnicities, notably Central/South Asian, East Asian, African, Hispanic, etc., remain comparatively limited, resulting in low precision of causal effect estimations within these ethnicities when using Mendelian randomization (MR). In this paper, we propose a trans-ethnic MR method, TEMR, to improve the statistical power and estimation precision of MR in a target population that is underrepresented, using trans-ethnic large-scale GWAS summary datasets. TEMR incorporates trans-ethnic genetic correlation coefficients through a conditional likelihood-based inference framework, producing calibrated p values with substantially improved MR power. In the simulation study, compared with other existing MR methods, TEMR exhibited superior precision and statistical power in causal effect estimation within the target populations. Finally, we applied TEMR to infer causal relationships between concentrations of 16 blood biomarkers and the risk of developing five diseases (hypertension, ischemic stroke, type 2 diabetes, schizophrenia, and major depression disorder) in East Asian, African, and Hispanic/Latino populations, leveraging biobank-scale GWAS summary data obtained from individuals of European descent. We found that the causal biomarkers were mostly validated by previous MR methods, and we also discovered 17 causal relationships that were not identified using previously published MR methods.