Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

Abstract

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans but with limited evidence in other ancestries. Here, we present a multi-ancestry proteome-wide MR analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the putative causal effects of 1,545 proteins on eight diseases in African (32,658) and European (1,219,993) ancestries and identified 45 and 7 protein-disease pairs with MR and genetic colocalization evidence in the two ancestries, respectively. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence in both ancestries and seven pairs with specific effects in the two ancestries separately. Integrating these MR signals with clinical trial evidence, we prioritized 16 pairs for investigation in future drug trials. Our results highlight the value of proteome-wide MR in informing the generalizability of drug targets for disease prevention across ancestries and illustrate the value of meta-analysis of biobanks in drug development.