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 limited data has made identification of causal proteins in other ancestries challenging. Here we present a multi-ancestry proteome-wide MR analysis pipeline based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the causal effects of 1,545 proteins on eight complex diseases in up to 32,658 individuals of African ancestries and 1.22 million individuals of European ancestries. We identified 45 and seven protein-disease pairs with MR and genetic colocalization evidence in the two ancestries respectively. 15 protein-disease pairs showed evidence of differential effects between males and females. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence of an effect in both ancestries, seven pairs with European-specific effects and seven with African-specific effects. Integrating these MR signals with observational and clinical trial evidence, we were able to evaluate the efficacy of one existing drug, identify seven drug repurposing opportunities and predict seven novel effects of proteins on diseases. Our results highlight the value of proteome-wide MR in informing the generalisability of drug targets across ancestries and illustrate the value of multi-cohort and biobank meta-analysis of genetic data for drug development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/21268473v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@120cdforg.highwire.dtl.DTLVardef@10b2d8aorg.highwire.dtl.DTLVardef@dae897org.highwire.dtl.DTLVardef@1dc2c9d_HPS_FORMAT_FIGEXP M_FIG C_FIG Notation: genome-wide association study (GWAS); Mendelian randomization (MR); primary open-angle glaucoma (POAG); idiopathic pulmonary fibrosis (IPF); chronic obstructive pulmonary disease (COPD); heart failure (HF), venous thromboembolism (VTE). European ancestry (EUR); African ancestry (AFR)*For the seven protein-disease associations, one association passed FDR threshold of 0.05 in proteome-wide MR, six additional associations passed FDR of 0.05 in the multi-ancestry comparison analysis. HighlightsO_LIA multi-ancestry proteome-wide Mendelian randomization (MR) analysis of 1,545 proteins on eight diseases in more than 1.26 million individuals from a disease GWAS meta-analysis of 19 biobanks. C_LIO_LIWe find evidence for putative causal effects in 45 protein-disease pairs in European ancestry and seven protein-disease pairs in African ancestry, with 15 pairs showing sex specific effects. C_LIO_LIWe identify evidence of causality for two protein-disease pairs that are common to both African and European ancestries, seven pairs with European-specific effects and seven pairs with African-specific effects. C_LIO_LITriangulating with clinical trial and observational evidence prioritizes seven new targets, seven drug repurposing opportunities and one existing drug target that generalise to African ancestry. C_LI