Genome-Wide Dissection of Shared Genetic Architecture Between Kidney Function and Pulmonary Function

Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) frequently present as comorbid conditions, while the underlying mechanisms remain largely unknown. Therefore, we aimed to explore the genetic correlations, shared genetic variants, and potential causal relationships between five kidney function traits (serum creatinine-based estimated glomerular filtration rate (eGFRcrea), cystatin C-based estimated glomerular filtration rate (eGFRcys), blood urea nitrogen (BUN), urinary albumin-to-creatinine ratio (UACR), urate) and four lung function traits (forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio (RATIO), and peak expiratory flow (PEF)), using data from UK Biobank and CKDGen Consortium with a total of about 1 004 040 participants. Our genome-wide cross-trait study found a strong genetic correlation between eGFRcys, urate, and FVC, and causal analysis using summary effect estimates further confirmed a negative causal effect of FVC on urate while identifying a positive causal effect of eGFRcrea on the RATIO. Cross-trait analysis uncovered 6 overlapped genes significantly shared across 20 trait pairs. Another 7 key genes were further found via transcriptome-wide association, colocalization, and fine-mapping analyses. These 13 key genes converged on four major biological functions, including immune response, endogenous compounds, developmental regulation, and olfactory receptors. Notably, six genes: RF00017, ZNF391, CYP1A1, CYP1A2, OR2J2, and OR14J1, showed novel links to both kidney and lung function traits. These findings uncover the genetic basis of kidney-lung interorgan communication and identify potential therapeutic strategies for reducing multi-system comorbidity.