A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced 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.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

Background: Age-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits. Methods: For each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression. Results: Of the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27-20.69%) and 16 of them were found to be significantly associated with AMD (Q-values \u3c 0.01, p values from \u3c 1.0 × 10-16 to 1.9 × 10-3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values \u3c 0.01, p values from 1.1 × 10-7 to 3.0 × 10-4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis. Conclusions: We demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common

Verteporfin therapy of subfoveal choroidal neovascularization in patients with age-related macular degeneration - Additional information regarding baseline lesion composition's impact on vision outcomes - TAP report No. 3

To explore how baseline lesion composition influenced vision outcomes in patients with age-related macular degeneration (AMD) undergoing photodynamic therapy with verteporfin (Visudyne) for subfoveal choroidal neovascularization (CNV) in the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy Investigation

Association between visual acuity and medical and non-medical costs in patients with wet age-related macular degeneration in France, Germany and Italy.

INTRODUCTION: Exudative ('wet') age-related macular degeneration (ARMD) is the major cause of blindness in Western developed countries. Treatments aimed at preserving vision are already available and new compounds are under development. Micro-economics information will be pivotal to justifying forthcoming investment. OBJECTIVE: This study sought to investigate the costs of exudative ARMD in patients who were actively treated at ophthalmology referral centres in three European countries: France, Germany and Italy. METHOD: This cross-sectional observational study was conducted in France, Germany and Italy in 2004. The following data were collected: ARMD description, visual acuity (VA), and the medical and non-medical resources used for ARMD in the preceding year. The economic perspective was that of society. ANOVA for cost variables estimated the impact of ARMD per eye, adjusted for sex and age. Both hospital and ambulatory eye centres were included. Patients with exudative ARMD were stratified into four levels of severity using VA thresholds of 20/200 for the worst eye (WE) and 20/40 for the best eye (BE). The main outcome measure was medical and non-medical costs. RESULTS: 360 patients were included (females 60%; mean age 77 years; mean interval since diagnosis 2.3 years). The two groups with the greatest difference in severity of VA loss consisted of BE >or= 20/40, WE >or= 20/200 (27.2% of patients) and BE <20/40, WE <20/200 (25.5% of patients). Total cost was two-thirds medical and one-third non-medical. Total costs increased with ARMD severity and were 1.1-2 times greater for severe disease compared with less severe disease. Average medical costs (2004 values) in France were euro 3714, compared with euro 1810 in Germany and euro 2020 in Italy, and showed slight increases with ARMD severity. Non-medical costs were significantly higher for patients with severe disease and highest in Germany. CONCLUSION: The impact of ARMD on costs was considerable and a positive correlation was found between total costs and ARMD severity. Differences among countries were partly explained by differences in customary care delivery