To identify novel Age-related macular degeneration (AMD) loci and establish polygenic prediction model DESIGN: Genome-wide association study (GWAS) and polygenic risk score (PRS).
Total of 64,885 European AMD cases and 568,740 controls (with overlapped samples) in UKB Biobank, GERA, International AMD consortium, FinnGen, published early-AMD GWAS in meta-analysis. 733 AMD European cases and 20,487 controls from the Canadian Longitudinal Study on Aging (CLSA). Non-Europeans from UK Biobank and GERA METHODS, INTERVENTION, OR TESTING: We conducted a multi-trait meta-analysis of genome-wide association studies (GWASs) comprising 64,885 AMD cases and 568,740 controls. We employed a multi-trait approach that dealt with sample overlap. We constructed a PRS for AMD based on these novel loci and previously reported AMD loci. We applied the PRS to non-overlapping data from the Canadian Longitudinal Study on Aging (733 AMD cases and 20,487 controls).
We identified several genetic SNPs associated with AMD and established PRS for AMD-risk prediction RESULTS: We identified 63 AMD risk loci alongside the well-established AMD loci CFH and ARMS2, including 9 loci that were not reported in previous GWAS, some of which have previously been linked to other eye diseases such as glaucoma (e.g. HIC1). We constructed a PRS for AMD based on these unreported loci and previously reported AMD loci. We applied the PRS to non-overlapping data from the CLSA (733 AMD cases and 20,487 controls). The PRS was constructed using a new PRS method PRS-CS and significantly improved the prediction accuracy of AMD risk compared to PRS from previously published datasets. We further showed that even people who carry all the well-known AMD risk alleles at CFH/ARMS2 vary considerably in their AMD risk (ranging from close to zero in low PRS individuals to >50% in high PRS individuals). Although our PRS is derived in individuals of European ancestry, the PRS shows potential for predicting risk in people of East Asian, South Asian, and Latino ancestry.
Our findings improve the knowledge of the genetic architecture of AMD and help achieve better accuracy in AMD prediction.

Copyright © 2023. Published by Elsevier Inc.