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

Abstract

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.

Variability in Retinal Neuron Populations and Associated Variations in Mass Transport Systems of the Retina in Health and Aging

“…The consequences of genetic mutations driving AMD is for instance often detected late in life; however, their effect on retinal and choroidal structures is likely to begin much earlier. An effective way to address this is to stratify subjects base on genetic susceptibility for disease (Pappas et al, 2021) and to exclude those at high risk from cross-sectional and longitudinal analyses.…”

Progression of Age-Related Macular Degeneration Among Individuals Homozygous for Risk Alleles on Chromosome 1 (CFH-CFHR5) or Chromosome 10 (ARMS2/HTRA1) or Both

“…The cohort was stratified into genetic groups using CFH-CFHR5 and ARMS2/HTRA1 diplotype combinations. Genetic groups were defined based on the risk-conferring variants rs1061170 ( CFH Y402H ) on Chr1 and rs10490924 ( ARMS2 A69S ) on Chr10 with the goal of isolating genetic AMD risk either at 1 of the loci or at both. Participants included in this study carried 2 risk alleles on Chr1 and no risk alleles on Chr10 (Chr1-risk group), 2 risk alleles on Chr10 without any risk alleles on Chr 1 (Chr10-risk group), or 2 risk alleles on both Chr 1 and Chr10 (Chr1&10-risk group) (eTable 1 in the Supplement ).…”

Distinctive cross-ancestry genetic architecture for age-related macular degeneration

“…We found that the deletion is largely out of phase with the CFH Y402H risk allele (D’=0.87) in AFR haplotypes; thus, it cannot fully explain the reduced effect size. Stratified by local ancestry, haplotypes in AA were analyzed using two models ( 38, 39 ), excluding SNPs that are rare in AFR haplotypes (Table S19) . While both models suggest that the putative risk haplotype may have a lower frequency in AFR compared to EUR, neither model demonstrated enrichment in cases with homozygous AFR local ancestry; they did, however, find haplotypes with enrichment in cases with homozygous EUR local ancestry.…”