Genome-Wide Association Study of Age-Related Macular Degeneration Reveals 2 New Loci Implying Shared Genetic Components with Central Serous Chorioretinopathy

Ophthalmology. 2023 Apr;130(4):361-372. doi: 10.1016/j.ophtha.2022.10.034. Epub 2022 Nov 22.


Purpose: To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population.

Design: Genome-wide association study (GWAS).

Participants: Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses.

Methods: We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants.

Main outcome measures: Associations of genetic variants with AMD.

Results: A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P < 5.0 × 10-8). Of these loci, 4 were known to be associated with AMD (CFH, C2/FB, TNFRSF10A, and ARMS2), and 2 were novel (rs4147157 near WBP1L and rs76228488 near GATA5). The newly identified associations were confirmed in a replication study (P < 0.01). After the meta-analysis of all datasets, we observed strong associations in these loci (P = 1.88 × 10-12 and P = 1.35 × 10-9 for meta-analysis for rs4147157 and rs76228488, respectively). When we looked up the associations in the reported central serous chorioretinopathy (CSC) GWAS conducted in the Japanese population, both loci were associated significantly with CSC (P = 4.86 × 10-3 and P = 4.28 × 10-3 for rs4147157 and rs76228488, respectively). We performed a genetic colocalization analysis for these loci and estimated that the posterior probabilities of shared causal variants between AMD and CSC were 0.39 and 0.60 for WBP1L and GATA5, respectively. Genetic correlation analysis focusing on the epidemiologically suggested clinical risk factors implicated shared polygenic architecture between AMD and smoking cessation (rg [the measure of genetic correlation] = -0.33; P = 0.01; false discovery rate, 0.099).

Conclusions: Our findings imply shared genetic components conferring the risk of both AMD and CSC.

Financial disclosure(s): Proprietary or commercial disclosure may be found after the references.

Keywords: Age-related macular degeneration; Central serous chorioretinopathy; Genome-wide association study; Polygenic architecture.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Central Serous Chorioretinopathy* / diagnosis
  • Central Serous Chorioretinopathy* / genetics
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Macular Degeneration* / genetics
  • Polymorphism, Single Nucleotide