Exploiting meta-analysis of genome-wide interaction with serum 25-hydroxyvitamin D to identify novel genetic loci...

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.

We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions.

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 (FEV₁) 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×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.

Our GWAS meta-analyses, accounting for interaction with 25(OH)D, revealed 30 genetic variants significantly associated with FEV₁ or FVC (P_2df <5.00×10^-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 influenced FEV₁ in both smoking groups (never smokers P_{1df interaction}<2.65×10^-4; ever smokers P_{1df interaction}<1.71×10^-5); rs3130553, rs2894186, rs79277477, and rs3130929 associations were only evident in never smokers, and the rs4678408 association was only found in ever smokers.

Genetic variant associations with lung function can be modified by 25(OH)D, and smoking history can further modify variant×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, influence lung function.