Proteome-Wide Genetic Study in East Asians and Europeans Identified Multiple Therapeutic Targets for Ischemic Stroke
Pang Yao, Mohsen Mazidi, Alfred Pozarickij, Andri Iona, Neil Wright, Kuang Lin, Iona Y. Millwood, Hannah Fry, Christiana Kartsonaki, Yiping Chen, Ling Yang, Huaidong Du, Daniel Avery, Dan Schmidt, Dianjianyi Sun, Pei Pei, Jun Lv, Canqing Yu, Michael Hill, Derrick Bennett, Robin G. Walters, Liming Li, Robert Clarke, Zhengming Chen, Junshi Chen, Rory Collins, Chen Wang, Richárd Pető, Ruth Boxall, Sushila Burgess, Ka Hung Chan, Johnathan Clarke, Ahmed Edris Mohamed, Simon Gilbert, Pek Kei Im, Maria Kakkoura, Hubert Lam, James H. Liu, Sam Morris, Qunhua Nie, Paul Ryder, Saredo Said, Becky Stevens, Iain Turnbull, Baihan Wang, Lin Wang, Xiaoming Yang, Xiao Han, Can Hou, Qingmei Xia, Chao Liu, Pei Pei, Dianjanyi Sun, Naying Chen, Duo Liu, Zhenzhu Tang, Ningyu Chen, Qilian Jiang, Jian Lan, Jian Lan, Mingqiang Li, Fanwen Meng, Jinhuai Meng, Jinhuai Meng, Yulu Qin, Ping Wang, Sisi Wang, Liuping Wei, Liyuan Zhou, Caixia Dong, Pengfei Ge, Xiaolan Ren, Zhongxiao Li, Enke Mao, Tao Wang, Hui Zhang, Hui Zhang, Jinyan Chen, Ximin Hu, Xiaohuan Wang, Zhendong Guo, Huimei Li, Huimei Li, Min Weng, Shukuan Wu, Shichun Yan, Mingyuan Zou, Xuedong Zhou, Ziyan Guo, Quan Kang, Yanjie Li, Bo Yu, Qinai Xu, Liang Chang, Lei Fan, Shixian Feng, Ding Zhang, Gang Zhou, Gang Zhou, Tian-You He
Abstract
BACKGROUND: Analyses of genomic and proteomics data in prospective biobank studies in diverse populations may discover novel or repurposing drug targets for stroke. METHODS: We extracted individual cis -protein quantitative trait locus for 2923 proteins measured using Olink Explore panel from a genome-wide association study in prospective China Kadoorie Biobank and UK Biobank, both established ≈20 years ago. These cis -protein quantitative trait loci were used in ancestry-specific 2-sample Mendelian randomization analyses of ischemic stroke (IS) in East Asians (n=22 664 cases) and Europeans (n=62 100 cases). We further undertook colocalization analyses to examine the shared causal variants of cis -protein quantitative trait locus with stroke, along with various downstream analyses (eg, phenome-wide association study, drug development lookups) to clarify mechanisms of action and druggability. RESULTS: In Mendelian randomization analyses, the genetically predicted plasma levels of 10 proteins were significantly associated with IS in East Asians (n=2) and Europeans (n=9), with 6 proteins (FGF5 [fibroblast growth factor 5], TMPRSS5 [transmembrane protease serine 5], FURIN, F11 [coagulation factor XI], ALDH2 [aldehyde dehydrogenase 2], and ABO [histo-blood group ABO system transferase]) showing positive and 4 (GRK5 [G protein-coupled receptor kinase 5], KIAA0319 [dyslexia-associated protein KIAA0319], PROCR [endothelial protein C receptor], and MMP12 [macrophage metalloelastase 12]) showing inverse associations, all directionally consistent between East Asians and Europeans. Colocalization analyses provided strong evidence (posterior probabilities for the H4 hypothesis ≥0.7) of shared genetic variants with IS for 9 out of 10 proteins (except ABO). Moreover, 8 proteins were also causally associated, in the expected directions, with systolic blood pressure (positive/inverse: 4/2), low-density lipoprotein cholesterol (1 positive), body mass index (1 inverse), type 2 diabetes (2/1), or atrial fibrillation (3/1). Phenome-wide association study analyses and lookups in knock-out mouse models confirmed their importance for IS or stroke-related traits (eg, hematologic phenotypes). Of these 10 proteins, 1 was not druggable (ABO), 3 had known primary (F11) or potentially repurposed (ALDH2, MMP12) drug targets for stroke, and 6 (PROCR, GRK5, FGF5, FURIN, KIAA0319, and TMPRSS5) had no evidence of any drug targets. CONCLUSIONS: Proteogenomic investigation in diverse ancestry populations identified the causal relevance of 10 proteins for IS, with several being potentially novel or repurposed targets that could be prioritized for further investigation.