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, most rare, protein-altering variant. 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. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 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.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate understanding of AMD biology and help design new therapies, we executed a collaborative genomewide association study, examining >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 genomic loci associated with AMD with p<5×10−8 and enriched for genes involved in regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include 7 loci reaching p<5×10−8 for the first time, near the genes COL8A1/FILIP1L, IER3/DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9/MIR548A2, and B3GALTL. A genetic risk score combining SNPs from all loci displayed similar good ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Purpose To describe the prevalence and interrelationships of epiretinal membranes, vitreomacular traction, macular cysts, paravascular cysts, lamellar macular holes, full-thickness macular holes, and visual impairment in a population-based study of older adults. Design Cross-sectional study. Participants There were 1913 participants aged 63–102 years at the 20-year Beaver Dam Eye Study follow-up examination in 2008–2010, of whom 1540 (2980 eyes) had gradable spectral-domain optical coherence tomography (SD-OCT) scans of the macula in at least one eye. Methods The presence of epiretinal membranes and other retinal lesions was determined by standardized grading of macular SD-OCT scans and photographs of three standard fields. Main Outcome Measures Epiretinal membranes, vitreomacular traction, macular cysts, paravascular cysts, lamellar macular holes, full-thickness macular holes, and visual impairment. Results Using SD-OCT the prevalences of epiretinal membranes (34.1%), vitreomacular traction (1.6%), macular cysts (5.7%), paravascular cysts (20.0%), lamellar macular holes (3.6%), and full-thickness macular holes (0.4%) were estimated. The prevalences of macular cysts (P<0.001), epiretinal membranes (P<0.001), and vitreomacular traction (P=0.005) increased with age, the prevalence of paravascular cysts (P=0.05) decreased with age, and the prevalence of lamellar macular holes was not associated with age (P=0.70). The prevalences of macular cysts, lamellar macular holes, and epiretinal membranes were higher in eyes with a history of cataract surgery. Macular cysts and epiretinal membranes were more common in eyes with retinal diseases such as proliferative diabetic retinopathy, retinal vein occlusion, and retinal detachment than in eyes without these conditions. Macular cysts, epiretinal membranes, and full-thickness macular holes were associated with visual impairment. While adjusting for age and sex, macular cysts (odds ratio [OR] 3.96; P<0.0001), paravascular cysts (OR 1.45, P=0.007), lamellar macular holes (OR 10.62; P<0.001), vitreomacular traction (OR 2.72, P=0.01) and visual impairment (OR 3.23; p<0.001) were more frequent in eyes with epiretinal membranes compared to eyes without. Conclusions Epiretinal membranes are associated with macular cysts, paravascular cysts, lamellar macular holes, vitreomacular traction, and visual impairment. Further follow-up will allow better understanding of the natural history of epiretinal membranes and vitreomacular traction and their relationships to the development of macular cysts and lamellar macular holes in the aging population.

Purpose To describe methods to harmonize the classification of age-related macular degeneration (AMD) phenotypes across four population-based cohort studies: the Beaver Dam Eye Study (BDES), Blue Mountains Eye Study (BMES), Los Angeles Latino Eye Study (LALES), and Rotterdam Study (RS). Methods AMD grading protocols, definitions of categories, and grading forms from each study were compared to determine whether there were systematic differences in AMD severity definitions and lesion categorization among the three grading centers. Each center graded the same set of 60 images using their respective systems to determine presence and severity of AMD lesions. A common five-step AMD severity scale and definitions of lesion measurement cutpoints and early and late AMD were developed from this exercise. Results Applying this severity scale changed the age-sex adjusted prevalence of early AMD from 18.7% to 20.3% in BDES, from 4.7% to 14.4% in BMES, from 14.1% to 15.8% in LALES, and from 7.5% to 17.1% in RS. Age-sex adjusted prevalences of late AMD remained unchanged. Comparison of each center’s grades of the 60 images converted to the consortium scale showed that exact agreement of AMD severity among centers varied from 61.0% to 81.4%, and one-step agreement varied from 84.7% to 98.3%. Conclusion Harmonization of AMD classification reduced categorical differences in phenotypic definitions across the studies, resulted in a new 5-step AMD severity scale, and enhanced similarity of AMD prevalence among four cohorts. Despite harmonization it may still be difficult to remove systematic differences in grading, if present.