Exploiting Meta-Analysis of Genome-Wide Interaction with Serum 25-Hydroxyvitamin D to Identify Novel Genetic Loci Associated with Pulmonary Function

Background: Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function. Objectives: We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions. Methods: We included 211,264 participants from the observational United Kingdom Biobank study with pulmonary function tests (PFTs), genome-wide genotypes, and 25(OH)D concentrations from 4 ancestral backgrounds - European, African, East Asian, and South Asian. Among PFTs, we focused on forced expiratory volume in the first second (FEV 1 ) and forced vital capacity (FVC) because both were previously associated with 25(OH)D. We performed genome-wide association study (GWAS) analyses that accounted for variant x 25(OH)D interaction using the joint 2 degree -of -freedom (2df) method, stratified by participants ' smoking history and ancestry, and meta -analyzed results. We evaluated interaction effects to determine how variant-PFT associations were modified by 25(OH)D concentrations and conducted pathway enrichment analysis to examine the biological relevance of our findings. Results: Our GWAS meta -analyses, accounting for interaction with 25(OH)D, revealed 30 genetic variants significantly associated with FEV 1 or FVC ( P (2df) < 5.00 x 10( -8) ) that were not previously reported for PFT-related traits. These novel variant signals were enriched in lung function -relevant pathways, including the p38 MAPK pathway. Among variants with genome-wide-significant 2df results, smoking -stratified meta -analyses identified 5 variants with 25(OH)D interactions that in fluenced FEV 1 in both smoking groups (never smokers P (1df interactio)n < 2.65 x 10( -4) ; ever smokers P (1df interaction) < 1.71 x 10 (-5) ); rs3130553, rs2894186, rs79277477, and rs3130929 associations were only evident in never smokers, and the rs4678408 association was only found in ever smokers. Conclusion: Genetic variant associations with lung function can be modified by 25(OH)D, and smoking history can further modify variant x 25(OH)D interactions. These results expand the known genetic architecture of pulmonary function and add evidence that gene -environment interactions, including with 25(OH)D and smoking, in fl uence lung function.