A genome-wide association study identifies novel genetic loci associated with pulmonary embolism

Abstract

Abstract Background Pulmonary embolism (PE) is a life-threatening cardiovascular condition. Studies showed that PE patients were associated with disorders of lipid metabolism and had higher triglyceride and lower HDL-C levels compared with healthy. We conducted the genome-wide association study to identify novel loci contributing to PE. Methods We conducted a large-scale GWAS of PE in 5,466 PE cases and 461,219 controls of European ancestry from the UK Biobank (466,685 participants total). We used genome-wide summary statistics to test for enrichment of functional annotations using ENRICHR. Example pathways included in Enrichr for testing include membership of genes in pathway databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG), Wikipathway, PANTHER, BioCarta or NCI-Nature pathways. We analyzed the pathways using combined score and p-values which were well validated by comparing to several methods. For pathway analyses, we considered a nominal P-value threshold of 0.05. Results We identified genome-wide significant genetic associations in 63 independent genetic loci for PE (P<5.0x10–7). Our findings for top pathways highlight that lipid metabolism (LIPC, LCAT, NPC2), caffeine metabolism (NAT2), and sudden cardiac death (ABCG8) related genetic loci play an important role in PE alongside genes already associated with coagulation-thrombosis pathway (VWF, THPO, PTPN11, INPP5D, UROS, HMBS) (all p-values p-values <0.05). Conclusion Our findings uncovered unexpected novel factors of PE etiology, suggesting novel mechanistic concepts of PE pathophysiology. Funding Acknowledgement Type of funding source: None