Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite the ever-increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis.

Age-related macular degeneration (AMD) is a common multifactorial disease in the elderly with a prominent genetic basis. Many risk variants have been identified, but the interpretation remains challenging. We investigated the genetic distribution of AMD-associated risk variants in a large European consortium, calculated attributable and pathway-specific genetic risks, and assessed the influence of lifestyle on genetic outcomes. Pooled analysis of cross-sectional data from the European Eye Epidemiology Consortium. Seventeen thousand one hundred seventy-four individuals 45 years of age or older participating in 6 population-based cohort studies, 2 clinic-based studies, and 1 case-control study. Age-related macular degeneration was diagnosed and graded based on fundus photographs. Data on genetics, lifestyle, and diet were harmonized. Minor allele frequencies and population-attributable fraction (PAF) were calculated. A total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) were constructed based on the dosage of SNPs and conditional β values; a lifestyle score was constructed based on smoking and diet. Intermediate and late AMD. The risk variants with the largest difference between late AMD patients and control participants and the highest PAFs were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Combining all genetic variants, the total genetic risk score ranged from -3.50 to 4.63 and increased with AMD severity. Of the late AMD patients, 1581 of 1777 (89%) showed a positive total GRS. The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS, 90% of patients with late disease), but risk in 3 pathways was most frequent (35% of patients with late disease). Lifestyle was a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least 2-fold. Genetic risk variants contribute to late AMD in most patients. However, lifestyle factors have a strong influence on the outcome of genetic risk and should be a strong focus in patient management. Genetic risks in ARMS2 and the complement pathway are present in most late AMD patients but are mostly combined with risks in other pathways.

Purpose: To document reticular pseudodrusen (RPD) using multimodal imaging in French elderly subjects. Methods: A total of 494 subjects (970 eyes) aged 77 years or more, from the Alienor study, were examined in 2011 and 2012. Reticular pseudodrusen were defined as definite if they were present with at least two imaging methods among color retinal photographs, macular cube (20° × 15°) of spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and infrared reflectance (IR). The Youden index was calculated as specificity + sensitivity − 1. Results: The prevalence of definite RPD was 13.4% and was higher among women (15.6%) than men (10.2%). It increased with age and reached almost 50% in subjects over 85 years. Infrared reflectance was the most sensitive technique (100%) and color fundus photography the least sensitive (34.5% at left eyes and 48.1% at right eyes). The best Youden index was obtained with IR (0.96 at both eyes) followed by SD-OCT (0.87 at right eye and 0.78 at left eye). Reticular pseudodrusen were present in 4.6% of eyes without AMD, 13.0% with early AMD1, 62.6% with early AMD2, 34.6% with atrophic AMD, and 8.1% with neovascular AMD. Reticular pseudodrusen were significantly associated with central and pericentral intermediate soft drusen (odds ratio [OR]: 2.14; 95% confidence interval [CI] = 1.11–4.14 and OR: 1.49; 95% CI = 1.16–1.90, respectively) and central large soft drusen (OR: 1.67; 95% CI = 1.16–2.42). Conclusions: Using multimodal imaging, the prevalence of RPD appears higher than previously reported in studies based on retinal photography only. Reticular pseudodrusen frequently accompany other signs of AMD. Infrared reflectance and SD-OCT appear to be particularly relevant methods to diagnose RPD.

Against a background of considerable epidemiological and other evidence implicating omega-3 fatty acids in the prevention of age-related macular degeneration (AMD), the negative results of the Age-Related Disease Study 2 (AREDS2) were unexpected. The possibility that the design, setting, intake or subjects of AREDS2 may not have permitted the prophylactic potential of omega-3 to be adequately demonstrated is considered. Epidemiological studies had indicated potential preventative effects of omega-3, and an earlier randomised prospective study (NAT2) showed that patients who achieved high red blood cell membrane EPA/DHA (eicosapentaenoic acid/docosahexaenoic acid) levels were significantly protected against AMD compared with those with permanently low EPA/DHA levels. Various methodological differences between these studies are considered. NAT2 included a true placebo group, whereas control subjects in AREDS2 received a nutritional formula already found to be effective in AREDS1, but no placebo for DHA/EPA supplementation. Differences in the handling of non-compliant subjects and the formulation of the test formulations are considered. Given these considerations, and other lines of evidence from laboratory and clinical studies, closing the chapter on omega-3 in AMD prevention may be premature.