Proteome-wide Mendelian randomization identifies candidate causal proteins for cardiovascular diseases

• DOI: 10.1101/2023.10.16.23297103
• Publication Date: 2023-10-18T04:30:20Z
• Authors: Chen Li; Nicolas De Jay; Supriya Sharma; Katrina A. Catalano; Emily R. Holzinger; Venkatesh Sridharan; Zhaoqing Wang; Lei Zhao; Joseph D. Szustak...; Ching-Pin Chang; Joseph C. Maranville; Erika M. Kvikstad
• Keywords: Mendelian Randomization; Proteome; Genome-wide Association Study

Abstract Background Cardiovascular diseases (CVD) remain the leading cause of death worldwide, while a lack clarity on underlying mechanisms has hindered development novel therapies. Integration human genetics and proteomics across different ancestries can provide novel, affordable, systematic approach for target identification prioritization. Methods Mendelian randomization was applied to unravel causal associations between 2,940 circulating proteins 21 CVD. Genome-wide summary statistics from largest genetic mapping plasma proteome meta-analyses CVD FinnGen, UK Biobank Japan were used. Forward reverse causation studied distinguish respective targets biomarkers. Genetic instruments Europeans East Asians derived separately cardiovascular outcomes in cohorts corresponding ancestries. We further prioritized drug by integrating biological, clinical population study evidence cross-database annotations literature review. Single-cell enrichment analysis phenome-wide causality scan performed understand mechanism action. Results found 221 candidate that impacted risk one or more through forward MR, 16 biomarkers whose expression levels affected MR (Bonferroni-adjusted P -value <= 0.05). largely non-overlapping among (only 2 overlapped: LGALS4 MMP12), suggesting distinct proteomic causes consequences Many (73.4%) identified are supported strong role immune response atherosclerotic lesion formation, angiogenesis vascular remodeling, myogenesis cardiac progenitor cell differentiation, energy metabolism. Single integration ADAM23 cardiomegaly, PAM stable angina pectoris ventricular arrythmia LPL peripheral artery disease, transcript enriched cardiomyocytes. Three protein functional groups highlighted their specific CVD, including blood coagulation fibrinolysis, proliferation myogenesis. Conclusions Our potential therapeutic distinguished them due causation. This provides genetics-based genes, foundational step towards full-scale biology-based discovery