Genome- and transcriptome-wide association studies show that pulmonary embolism is associated with bone-forming proteins

ABSTRACT

Background

Pulmonary embolism (PE) is a leading cause of death in stroke patients and a severe health burden worldwide. There is a pressing need to understand the mechanisms by which it occurs and to identify at-risk patients efficiently and accurately.

Methods

First, based on data from GWAS in European populations, we performed a linkage disequilibrium score regression (LDSC) analysis of plasma proteins and PE in 3,283 individuals and additionally analyzed the genetic association between PE and fracture. Then, we performed a TWAS on PE GWAS data using skeletal muscle and blood for gene expression references. Finally, we validated the genetic correlation between PE and human plasma proteins by co-matching the genes encoding the identified proteins and those identified using TWAS with the differentially expressed genes obtained from mRNA expression profiling of PE.

Results

We identified five plasma proteins associated with PE, including hydroxycarboxylic acid receptor 2, defensin 118, and bone morphogenetic protein (BMP) 7, as well as a relationship between PE and fracture. Comparison of genes encoding these proteins with genes obtained from TWAS and then with differentially expressed genes obtained from PE mRNA expression profiling revealed that PE was highly correlated with the BMP family of genes.

KEYWORDS:

• Pulmonary embolism
• GWAS
• BMP
• LDSC
• TWAS

Abbreviations

PE: Pulmonary embolism; LDSC: Linkage disequilibrium score regression; GWAS: Genome-wide association study; TWAS: Transcriptome-wide association studies; DEGs: Differentially expressed genes; BMP: Bone Morphogenetic Protein; DVT: Deep vein thrombosis; GTEx: Genotype-Tissue Expression.

Acknowledgments

We are indebted to all the individuals who participated in, or helped with, our research.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Author contributions

Author Ruoyang Feng, Mengnan Lu, Yanni Yang, Pan Luo, Lin Liu, Ke Xu, Peng Xu designed the study.

Additional information

Funding

This work was supported by the National Natural Scientific Foundation of China (82072432, 81772410).