Exploring novel risk loci for heart failure and the shared genetic etiology with blood lipids, blood pressure, and blood glucose: a large-scale multi-trait association analysis

Background The comprehensive exploration of genomic risk loci for heart failure (HF) remains constrained, and the genetic role of blood lipids (BL), blood pressure (BP) and blood glucose (BG) in HF has not been fully characterized. Methods We first assessed the global and local genetic correlations between HF and the quantitative traits of BL, BP, and BG. We then employed multi-trait association analysis and multi-trait colocalization analysis to identify novel and pleiotropic genomic risk loci for HF. Furthermore, we explored potential genes, pathways, tissues, and cells associated with HF involving BL, BP, and BG. Lastly, we investigated potential therapeutic targets for HF. Findings We found extensive global and local genetic correlations between HF and the traits of BL, BP, and BG. Multi-trait association analysis successfully identified 154 novel genomic risk loci for HF. Multi-trait colocalization analysis further revealed 46, 35, and 14 co-localized loci shared by HF with BL, BP, and BG, respectively. We found that the loci shared by HF with these traits rarely overlapped, indicating distinct shared mechanisms. Gene-mapping, gene-based, and transcriptome-wide association analyses prioritized noteworthy candidate genes (such as LPL, GRK5, and TNNC1) for HF. In enrichment analysis, HF exhibited comparable characteristics with cardiovascular traits and metabolic correlated to BL, BP, and BG. We provided genetic evidence for putative drugs, and highlighted 33 robust potential protein targets. Interpretation These findings will provide biological insights into the pathogenesis for HF, and benefit the development of preventive or therapeutic drugs for HF.