Research from JAMA Ophthalmology — Causes and Prevalence of Visual Impairment Among Adults in the United States

Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene ( HF1 / CFH ), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of ≈900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, χ ² = 26.1 and P = 3.2 × 10 ^-7 and Y402H, χ ² = 54.4 and P = 1.6 × 10 ^-13 ). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.

Iris Heid, Gonçalo Abecasis, Sudha Iyengar and colleagues report the results of a large genome-wide association meta-analysis of macular degeneration based on over 43,000 subjects. They identify 16 new risk loci, including some very rare coding variants. Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10−8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10−10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Purpose: To determine the risk between degree of myopia and myopic macular degeneration (MMD), retinal detachment (RD), cataract, open angle glaucoma (OAG), and blindness. Methods: A systematic review and meta-analyses of studies published before June 2019 on myopia complications. Odds ratios (OR) per complication and spherical equivalent (SER) degree (low myopia SER < –0.5 to > –3.00 diopter [D]; moderate myopia SER ≤ –3.00 to > –6.00 D; high myopia SER ≤ –6.00 D) were calculated using fixed and random effects models. Results: Low, moderate, and high myopia were all associated with increased risks of MMD (OR, 13.57, 95% confidence interval [CI], 6.18–29.79; OR, 72.74, 95% CI, 33.18–159.48; OR, 845.08, 95% CI, 230.05–3104.34, respectively); RD (OR, 3.15, 95% CI, 1.92–5.17; OR, 8.74, 95% CI, 7.28–10.50; OR, 12.62, 95% CI, 6.65–23.94, respectively); posterior subcapsular cataract (OR, 1.56, 95% CI, 1.32–1.84; OR, 2.55, 95% CI, 1.98–3.28; OR, 4.55, 95% CI, 2.66–7.75, respectively); nuclear cataract (OR, 1.79, 95% CI, 1.08–2.97; OR, 2.39, 95% CI, 1.03–5.55; OR, 2.87, 95% CI, 1.43–5.73, respectively); and OAG (OR, 1.59, 95% CI, 1.33–1.91; OR, 2.92, 95% CI, 1.89–4.52 for low and moderate/high myopia, respectively). The risk of visual impairment was strongly related to longer axial length, higher myopia degree, and age older than 60 years (OR, 1.71, 95% CI, 1.07–2.74; OR, 5.54, 95% CI, 3.12–9.85; and OR, 87.63, 95% CI, 34.50–222.58 for low, moderate, and high myopia in participants aged >60 years, respectively). Conclusions: Although high myopia carries the highest risk of complications and visual impairment, low and moderate myopia also have considerable risks. These estimates should alert policy makers and health care professionals to make myopia a priority for prevention and treatment.