The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium

Ophthalmology. 2022 Jul;129(7):752-764. doi: 10.1016/j.ophtha.2022.02.026. Epub 2022 Mar 1.


Purpose: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium.

Design: Pooled analysis of 4 case-control and 6 cohort studies.

Participants: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium.

Methods: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan-Meier analyses in population-based cohorts.

Main outcome measures: Age-related macular degeneration features and stage.

Results: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5-11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4-13.3), and of mixed late AMD was 12.2 (95% CI, 7.3-20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0-11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 μm (OR, 1.2; 95% CI, 0.9-1.7), but risks increased significantly for soft drusen ≥ 125 μm (OR, 2.1; 95% CI, 1.5-3.0), up to an OR of 7.2 (95% CI, 3.8-13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2-5.4); risks of other characteristics were not different.

Conclusions: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.

Keywords: ARMS2; Age-related macular degeneration; Europe; Genetics; HTRA1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Choroidal Neovascularization* / genetics
  • Complement Factor H / genetics
  • Genotype
  • High-Temperature Requirement A Serine Peptidase 1 / genetics
  • Humans
  • Macular Degeneration* / diagnosis
  • Macular Degeneration* / epidemiology
  • Macular Degeneration* / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Proteins / genetics
  • Retinal Drusen* / genetics
  • Risk Factors


  • ARMS2 protein, human
  • Proteins
  • Complement Factor H
  • High-Temperature Requirement A Serine Peptidase 1
  • HTRA1 protein, human