Deciphering gene-smoking interactions in age-related macular degeneration through cross-biobank genomic integration

This study aims to identify genetic loci associated with age-related macular degeneration (AMD) and assess the interaction between genetic susceptibility and smoking history.

A meta-analysis of discovery genome-wide association studies (GWASs), involving a total of 42542 AMD patients and 920322 controls from four large-scale European cohorts, was conducted using METAL, a software tool commonly used for meta-analysis of GWAS. A polygenic risk score (PRS) was derived from the meta-analysis results for 331281 UK Biobank participants. Cox proportional hazards models evaluated interactions between genetic predisposition and smoking history at both PRS and variant levels. Logistic regression models examined plasma complement protein profiles across AMD PRS and smoking status groups.

We identified two novel risk loci, OCA2 melanosomal transmembrane protein (OCA2) and nitric oxide associated 1 (NOA1). Incorporating the PRS significantly enhanced AMD risk prediction in 331281 UK Biobank participants, with the area under the curve (AUC) increasing from 0.74 to 0.76 (p=2×10^-16). During a mean follow-up of 13.6 years, Cox models revealed significant additive (relative excess risk due to interaction, RERI=0.13; 95% CI: 0.06-0.19; attributable proportion, AP=0.08; 95% CI: 0.04-0.13; synergy index, SI=1.33; 95% CI: 1.13-1.56) and multiplicative interactions (hazard ratio, HR=1.08; 95% CI: 1.03-1.14, p=2.65×10^-3) between PRS and smoking history. Variant-level interactions were prominent at complement factor H (CFH) and complement factor I (CFI) loci. Individuals who have ever smoked and high PRS exhibited dysregulated plasma proteins in the alternative, classical and lectin complement pathways.

This study revealed the genetic architecture of AMD and highlighted the synergistic effects of smoking and genetic risk, emphasizing the potential need to integrate genetic assessments into prevention strategies.