Abstract
The coexistence of coronary artery disease (CAD) and chronic kidney disease (CKD) implies overlapped genetic foundation. However, the common genetic determination between the two diseases remains largely unknown. Relying on summary statistics publicly available from large scale genome-wide association studies (n = 184,305 for CAD and n = 567,460 for CKD), we observed significant positive genetic correlation between CAD and CKD (rg = 0.173, p = 0.024) via the linkage disequilibrium score regression. Next, we implemented gene-based association analysis for each disease through MAGMA (Multi-marker Analysis of GenoMic Annotation) and detected 763 and 827 genes associated with CAD or CKD (FDR < 0.05). Among those 72 genes were shared between the two diseases. Furthermore, by integrating the overlapped genetic information between CAD and CKD, we implemented two pleiotropy-informed informatics approaches including cFDR (conditional false discovery rate) and GPA (Genetic analysis incorporating Pleiotropy and Annotation), and identified 169 and 504 shared genes (FDR < 0.05), of which 121 genes were simultaneously discovered by cFDR and GPA. Importantly, we found 11 potentially new pleiotropic genes related to both CAD and CKD (i.e., ARHGEF19, RSG1, NDST2, CAMK2G, VCL, LRP10, RBM23, USP10, WNT9B, GOSR2, and RPRML). Five of the newly identified pleiotropic genes were further repeated via an additional dataset CAD available from UK Biobank. Our functional enrichment analysis showed that those pleiotropic genes were enriched in diverse relevant pathway processes including quaternary ammonium group transmembrane transporter, dopamine transport. Overall, this study identifies common genetic architectures overlapped between CAD and CKD and will help to advance understanding of the molecular mechanisms underlying the comorbidity of the two diseases.
Highlights
Both coronary artery disease (CAD) and chronic kidney disease (CKD) are the leading causes of death and disability worldwide, representing serious global public health threats (Kessler et al, 2013; Inrig et al, 2014; Ene-Iordache et al, 2016; Levin et al, 2017; Musunuru and Kathiresan, 2019)
The genomic inflation factor is 1.015 for CAD and 1.143 for CKD, which, together the LDSC intercept [i.e., 0.903 (SE = 0.005) for CAD and 1.134 (SE = 0.007) for CKD], suggests that the weak inflation of the χ2 statistic of CKD is primarily due to polygenicity rather than population stratification or cryptic
It is found that all the estimates of rg in those categories are positive, again supporting the statement that CAD and CKD have overlapped genetic foundation
Summary
Both coronary artery disease (CAD) and chronic kidney disease (CKD) are the leading causes of death and disability worldwide, representing serious global public health threats (Kessler et al, 2013; Inrig et al, 2014; Ene-Iordache et al, 2016; Levin et al, 2017; Musunuru and Kathiresan, 2019). It is often observed that CKD patients encounter an increased risk of CAD and CAD is in turn a major cause of death for CKD patients (Tonelli et al, 2012). The endothelial dysfunction is closely related to cardiovascular diseases and plays an important role in all stages of atherosclerosis (Ross, 1999). The role of CAD in CKD is widely studied; for example, the endothelial dysfunction in the development of CKD was well documented (Moody et al, 2012). For CKD patients not yet requiring renal replacement therapy, the probability of developing MACE is much higher than reaching end-stage renal disease (ESRD) and requiring renal replacement therapy (Foley et al, 2005)
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