Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci

Hum Genomics. 2021 Sep 25;15(1):60. doi: 10.1186/s40246-021-00359-8.


Background: Single-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26 (Chr10 locus).

Results: By refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes.

Conclusions: Our study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.

Keywords: ARMS2/HTRA1; Age-related macular degeneration; CFH-CFHR5; Diplotype; Genetic association study; Haplotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Chromosomes / genetics
  • Complement Factor H / genetics
  • Complement System Proteins / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Haplotypes / genetics
  • High-Temperature Requirement A Serine Peptidase 1 / genetics*
  • Humans
  • Linkage Disequilibrium
  • Macular Degeneration / genetics*
  • Macular Degeneration / pathology
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Proteins / genetics*


  • ARMS2 protein, human
  • CFH protein, human
  • CFHR5 protein, human
  • Proteins
  • Complement Factor H
  • Complement System Proteins
  • High-Temperature Requirement A Serine Peptidase 1
  • HTRA1 protein, human