Exploring shared genetic effects that are minimally impacted by environmental factors offers deeper insights into the common biological basis linking associations underlying two different phenotypes. To our knowledge, this study represents the first large-scale genome-wide cross-trait analysis, delving into the shared genetic basis between pulmonary function and three prevalent CVD. These findings provide evidence of global and regional shared genetic basis, confirming an intrinsic correlation between these traits. Furthermore, the genetic overlap was dissected into pleiotropy and causal relationships, reflected by pleiotropic loci and genes revealed by CPASSOC or TWAS, and causal relationships demonstrated by MR analyses.
Overall, statistically significant global genetic correlations were confirmed, with a shared genetic contribution of 16–20% between pulmonary function and CVD. Significant local signals detected in multiple specific genomic regions further validate the overall genetic correlation, emphasizing a crucial shared biological basis. The local regional analysis largely aligns with the global genetic analysis and MR analysis. Among the identified 24 shared local regions, 19 display a negative correlation between impaired lung function and CVD.
The significantly global and regional genetic correlations could result from the pleiotropic effects of genetic elements shared between lung function and CVD or indicate a potential causal link between lung function and CVD. In our subsequent analysis, we identified 57 independent loci influencing susceptibility to both lung function and CVD, reflecting considerable genetic pleiotropy. It is notable that many of the observed cross-trait effects have previously been associated with inflammation (ILF3, NOS3, SKI) [52–54], stress responses (IP6K2, BAG3) [55, 56], and the blood system (KIAA1462, ABO, CFDP1, WDR12) [46, 57–59]. These findings shed light on potential mechanistic pathways linking lung function with CVD. Through colocalization analysis, multiple genes (ABO, BAG3, TEX41, KIAA1462, INPP5B, ZC3HC1) exhibited a shared causal mechanism (PPH4 > 0.5). In this study, we specifically focused on two interesting examples, KIAA1462 (PPH4 = 0.65) and BAG3 (PPH4 = 0.99), both shared between impaired lung function and CVD.
KIAA1462 (also known as JCAD, a gene encoding a protein associated with CAD) has recently been identified as a new risk gene for CAD [13]. In CAD patients, the absence of KIAA1462 inhibits vascular inflammation, improves vascular activity, and suppresses atherosclerosis [57]. Additionally, its function in vascular development and tissue balance is associated with the occurrence of diseases related to impaired lung function [60]. Previous studies have shown decreased expression levels of KIAA1462 in COPD patients compared to non-COPD controls [60]. Furthermore, KIAA1462 has been identified as a gene associated with lung function [16]. BAG3 possesses multifaceted regulation abilities in major biological processes such as apoptosis, development, cellular cytoskeleton organization, and autophagy, thereby mediating adaptive responses of cells to stress stimuli [61]. In the heart, BAG3 inhibits cell apoptosis, promotes autophagy, and maintains myofibrillar structure [62]. Particularly, recent experimental studies suggest that BAG3-mediated sarcomere turnover forms the basis for maintaining myofilament function and is associated with the development of HF [63, 64]. Moreover, BAG3 expression levels in COPD blood samples are higher than in normal blood samples, potentially influencing COPD development by regulating autophagy [65]. Further experimental research is needed to provide more detailed functional annotations for these identified genetic loci, especially those related to impaired lung function and CVD.
Combined GWAS summary data with GTEx tissue expression data, the TWAS analysis elucidated putative shared mechanisms between impaired lung function and CVD at the gene-tissue level. Consistent with findings from CPASSOC, multiple genes associated with inflammation (ILF3), stress response (IP6K2), and the blood system (ABO, WDR12, SH3PXD2A) were shared between lung function and CVD. Furthermore, TWAS identified multiple genes in brain-related tissues (such as cortex, basal ganglia, hypothalamus), indicating a potential neurobiological mechanism. Consistently, GTEx tissue enrichment analysis corroborated these findings, demonstrating significant enrichment of shared genes in brain-related tissues. This confirms well-established knowledge that both impaired lung function and CVD are associated with multiple brain-related disorders [66, 67]. Indeed, heart-brain interactions and brain-lung axis has been recently highlighted for complex communications in regulating multiple systemic diseases. For example, impaired lung function could potentially lead to an increased risk of brain disorders, such as depression and cognitive dysfunction [68], while individuals with these brain disorders exhibit a significantly elevated risk of CVD [66]. Additionally, we observed shared regulatory features in the digestive system, especially between lung function and CAD. Observational studies have reported comorbidities between respiratory diseases (i.e., COPD) and digestive diseases [i.e., gastroesophageal reflux disease and inflammatory bowel disease (IBD)], and related genetic overlap has been also reported in recent genetic research [69–71]. Moreover, the significance of the digestive system in the development of CVD is increasingly recognized [72]. For instance, the systemic inflammatory state in patients with IBD promotes atherosclerosis and mediates the occurrence and progression of CAD [72]. In summary, these shared biological pathways between impaired lung function and CVD offer therapeutic strategies for clinical practice of the coexisting conditions. Further research is warranted to comprehensively unravel these intricate mechanisms.
Employing a comprehensive bidirectional MR analysis, this study reveals a significant causal association between impaired lung function and an elevated risk of CAD and stroke. These findings are largely consistent with observations from several prospective studies, where individuals with impaired lung function exhibited a higher risk of developing CVD [4, 5, 73, 74]. Furthermore, our MR analysis not only corroborates previous findings [17–19], but also extends them in two critical aspects. Through the utilization of the multivariable MR, we minimized the impact of confounders. Additionally, we mitigated the influence of reverse causality by utilizing a bidirectional MR design. Our findings confirm the detrimental impact of impaired lung function on the risk of CVD and convey a crucial message that could provide insights for clinical and public health practices. Firstly, our work sheds light on the potential health risk in population with to impaired lung function. Secondly, this study provides evidence supporting personalized CVD screening that considers impaired lung function as a causal risk factor in the future for potentially enhancing preventive measures.
Several limitations need to be acknowledged. Firstly, our findings were limited to population of European ancestry. Future studies involving other ancestry groups were warranted. Secondly, he two-sample MR analysis assumes a linear impact of exposure on the outcome [35]. However, recent study has suggested a potential U-shaped relationship between lung function and CVD risk, which could introduce complexities not captured in our analysis [73]. Thirdly, the genetic effects on lung function and CVD were predominantly derived from cross-sectional studies within the population, potentially lacking insights into longitudinal progression. Understanding alterations in lung function over time and their relationship with CVD progression requires further investigation. Lastly, our study utilized summary-level data due to inherent data limitations. While leveraging summary-level data offers the advantage of larger sample size, thereby enhancing statistical power in estimating causality, it is crucial to acknowledge its limitations. Unlike individual-level data, summary-level data lack the capacity to consider specific confounding factors unique to individual, such as local socioeconomic conditions, medical situations, and other individual-level factors. Future investigations should corroborate our findings using independent data.
In conclusion, our study contributes significantly to the existing knowledge of the phenotypic association between impaired lung function and CVD by providing the evidence of genetic correlation, identifying pleiotropic loci, and revealing a potential causal association where impaired lung function may increase the risk of CVD. These findings shed light on possible biological mechanisms linking impaired lung function and CVD, offering valuable insights for future research endeavors aimed at reducing CVD risk.