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

## TL;DR

This study finds new genetic links to age-related macular degeneration and shows how smoking interacts with genetic risk to worsen the disease.

## Contribution

The study identifies two novel genetic loci and demonstrates significant gene-smoking interactions in AMD risk.

## Key findings

- Two novel risk loci, OCA2 and NOA1, were identified for age-related macular degeneration.
- Smoking and high polygenic risk score synergistically increase AMD risk, with significant additive and multiplicative interactions.
- Smokers with high genetic risk show dysregulated complement pathways in plasma proteins.

## Abstract

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.