Common and rare genetic risk variants in age-related macular degeneration and genetic risk score in the Coimbra eye study

Purpose To determine the contribution of common and rare genetic variants in age-related macular degeneration (AMD) in a Portuguese population from the Coimbra Eye Study (CES), and the genetic risk score (GRS). Methods Participants underwent ophthalmologic examination and imaging. A centralized reading centre performed AMD staging. Genetic sequencing was carried out with the EYE-RISK assay. Sixty-nine single nucleotide polymorphisms (SNPs) were genotyped and tested for association with AMD. Case-control and progression-to-AMD analyses were performed using logistic regression to assess allelic odds ratio (OR) at a 95% confidence interval (CI) for each variant. GRS was calculated for cases/controls and progressors/non-progressors. Cumulative impact of rare variants was compared between cases/controls using logistic regression. Results In case-control analysis (237 cases/640 controls) variants associated with risk of disease were: ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876, SLC16A8 rs8135665, TGFBR1 rs1626340. Major risk variants ARMS2/HTRA1 rs3750846, CFH rs570618 and C3 rs2230199 had unexpected lower allele frequency (AF), and the highest risk-conferring variant was a rare variant, CFH rs35292876 (OR, 2.668; p-value = 0.021). In progression-to-AMD analysis (137 progressors/630 non-progressors), variants associated with risk of progression were ARMS2 rs10490924, ARMS2_HTRA1 rs3750846, CFH rs35292876. GRS of cases/controls was 1.124 +/- 1.187 and 0.645 +/- 1.124 (p-value < 0.001), and of progressors/non-progressors was 1.190 +/- 1.178 and 0.669 +/- 1.141 (p-value < 0.001). Higher proportion of pathogenic rare CFH variants was observed in cases (OR, 9.661; p-value < 0.001). Conclusions Both common and rare variants were associated with AMD, but a CFH rare variant conferred the highest risk of disease while three major risk variants had a lower-than-expected AF in our population originary from a geographic region with lower prevalence of AMD. GRS was still significantly higher in AMD patients. Damaging CFH rare variants were cumulatively more common in AMD cases.