Bidirectional genetic links between chronic obstructive pulmonary disease and frailty: Genome-wide association study insights.

Abstract

Recent research underscores a potential correlation between chronic obstructive pulmonary disease (COPD) and frailty, suggesting a shared genetic foundation. However, specific genetic factors and mechanisms underlying this association remain unclear. This study aimed to explore genetic connections between COPD and frailty using genome-wide association studies to enhance our understanding and improve clinical management and prevention strategies for these conditions. We utilised summary statistics for genome-wide association studies to examine the genetic correlations between COPD and frailty using linkage disequilibrium score regression. Local genetic correlations were evaluated using the ρ-heritability estimates from summary statistics method. Using the established two-sample Mendelian randomization approach, causal relationships have been identified. Shared genetic variants were quantified using a bivariate causal mixture model. Shared loci and single nucleotide polymorphisms were identified by conjoint false discovery rate (conjFDR). Gene enrichment and transcriptome-wide association studies (TWAS) were conducted to explore potential transcriptomic associations across tissues. We observed a significant genetic correlation between COPD and frailty (Rg =  0.4324, P =  6.09 ×  10 - 26). MiXeR estimated 3,200-shared causal variants. Additionally, we discovered 16 shared loci linked to 91 genes, offering novel insights into gene expression across diverse tissues. The TWAS revealed 25 shared genes, representing a significant advance in understanding the genetic overlap between COPD and frailty. Furthermore, out of the 25 SNPs identified through TWAS, 4 overlapped with the lead SNPs, specifically [HLA-DRB1, PBX3, SLC22A5/OCTN2, SLMAP]. Our study shows a common genetic foundation for COPD and frailty, identifying multiple shared loci and offering insights into their underlying causal connections. These findings enhance our understanding of the biological mechanisms linking these conditions and may guide future research and treatment strategies for related diseases.