Distinct Genetic Risk Profile of the Rapidly Progressing Diffuse-Trickling Subtype of Geographic Atrophy in Age-Related Macular Degeneration (AMD).

PURPOSE: To genetically characterize a subphenotype of geographic atrophy (GA) in AMD associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence imaging. METHODS: Patients from the Fundus Autofluorescence in Age-Related Macular Degeneration Study were phenotyped for diffuse-trickling GA (dt-GA; n = 44). DNA was analyzed for 10 known AMD-associated genetic variants. A genetic risk score (GRS) was calculated and compared with patients with nondiffuse-trickling GA (ndt-GA; n = 311) and individuals from the 1000 genomes project (1000G; n = 267). Given the phenotypic overlap between diffuse-trickling and late-onset retinal degeneration (LORD), all C1QTNF5 exons and their exon/intron boundaries were sequenced. RESULTS: A statistically significant difference in allele frequencies between dt-GA and ndt-GA were found for CFH:rs1061170 and CFH:rs800292 (Pcorrected = 0.03). The ARMS2 variant rs10490924 was significantly more frequent in dt-GA than in 1000G individuals (Pcorrected < 0.01). The GRS of dt-GA patients was in-between the score of the 1000G individuals and that of patients with ndt-GA, significantly differing from both (Pcorrected <0.01). Sequencing of C1QTNF5 revealed 28 unique variants although none showed a statistically significant association with dt-GA when compared with 1000G individuals. CONCLUSIONS: The dt-GA phenotype shows a remarkably different genetic risk profile from other GA phenotypes secondary to AMD. Disease-associated C1QTNF5 mutations were not identified. Together, these results suggest that the dt-GA phenotype is associated with a genetic background substantially different from other GA phenotypes and underlines the necessity to refine the clinical phenotyping, specifically when aiming for individualized therapies in AMD.

A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD).

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined PADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (Pdiff = 0.0032) in that it was clearly confined to females with genome-wide significance [PADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: PADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis.

Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Progression of age-related geographic atrophy: role of the fellow eye.

PURPOSE. To evaluate the role of fellow eye status in determining progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS. A total of 300 eyes with GA of 193 patients from the prospective, longitudinal, natural history FAM Study were classified into three groups according to the AMD manifestation in the fellow eye at baseline examination: (1) bilateral GA, (2) early/intermediate AMD, and (3) exudative AMD. GA areas were quantified based on fundus autofluorescence images using a semiautomated image-processing method, and progression rates (PR) were estimated using two-level, linear, mixed-effects models. RESULTS. Crude GA-PR in the bilateral GA group (mean, 1.64 mm(2)/y; 95% CI, 1.478-1.803) was significantly higher than in the fellow eye early/intermediate group (0.74 mm(2)/y, 0.146-1.342). Although there was a significant difference in baseline GA size (P = 0.0013, t-test), and there was a significant increase in GA-PR by 0.11 mm(2)/y (0.05-0.17) per 1 disc area (DA; 2.54 mm(2)), an additional mean change of -0.79 (-1.43 to -0.15) was given to the PR beside the effect of baseline GA size. However, this difference was only significant when GA size was ≥1 DA at baseline with a GA-PR of 1.70 mm(2)/y (1.54-1.85) in the bilateral and 0.95 mm(2)/y (0.37-1.54) in the early/intermediate group. There was no significant difference in PR compared with that in the fellow eye exudative group. CONCLUSIONS. The results indicate that the AMD manifestation of the fellow eye at baseline serves as an indicator for disease progression in eyes with GA ≥ 1 DA. Predictive characteristics not only contribute to the understanding of pathophysiological mechanisms, but also are useful for the design of future interventional trials in GA patients.