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

Area of Science:

• Genetics
• Pulmonology
• Nephrology

Background:

• Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) frequently co-occur, but the underlying genetic mechanisms are poorly understood.
• Understanding shared genetic factors is crucial for addressing multi-system comorbidities.

Purpose of the Study:

• To investigate genetic correlations, shared variants, and causal relationships between kidney function traits (e.g., eGFRcrea, urate) and lung function traits (e.g., FVC, FEV1).
• To identify key genes and biological pathways involved in kidney-lung interorgan communication.

Main Methods:

• Genome-wide cross-trait analysis using data from UK Biobank and CKDGen Consortium (approx. 1 million participants).
• Summary-based Mendelian randomization for causal inference.
• Transcriptome-wide association, colocalization, and fine-mapping analyses to identify key genes.

Main Results:

• Strong genetic correlation found between cystatin C-based estimated glomerular filtration rate (eGFRcys), urate, and forced vital capacity (FVC).
• Causal analysis revealed a negative causal effect of FVC on urate and a positive causal effect of serum creatinine-based estimated glomerular filtration rate (eGFRcrea) on the FEV1/FVC ratio (RATIO).
• Identified 13 key genes, including novel links for RF00017, ZNF391, CYP1A1, CYP1A2, OR2J2, and OR14J1, converging on immune response, endogenous compounds, developmental regulation, and olfactory receptors.

Conclusions:

• Uncovered the genetic basis of kidney-lung interorgan communication.
• Identified novel genes and biological pathways potentially mediating CKD-COPD comorbidity.
• Findings suggest potential therapeutic strategies for managing multi-system diseases.