Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

PurposeAge-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future.DesignMeta-analysis of prevalence data.ParticipantsA total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe.MethodsAMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV).Main Outcome MeasuresPrevalence of early and late AMD, BCVA, and number of AMD cases.ResultsPrevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95% CI 13.6%–21.5%) in those aged ≥85 years; for late AMD these figures were 0.1% (95% CI 0.04%–0.3%) and 9.8% (95% CI 6.3%–13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer ≥80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million.ConclusionWe observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti–vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Genetic and epidemiologic studies have shown that lipid genes and High Density Lipoproteins (HDL) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relation to AMD in a large European dataset, and investigated whether this relationship is driven by certain sub fractions. Design: (Pooled) analysis of cross-sectional data. Participants: 30,953 individuals aged 50+ participating in the E3 consortium; and 1530 individuals from the Rotterdam Study with lipid sub fraction data. Methods: In E3, AMD features were graded per eye on fundus photographs using the Rotterdam Classification. Routine blood lipid measurements were available from each participant. Data on genetics, medication and confounders such as body mass index, were obtained from a common database. In a subgroup of the Rotterdam Study, lipid sub fractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random-effect were used to estimate the associations. Main Outcome Measures: early, late or any AMD, phenotypic features of early AMD, lipid measurements. Results: HDL was associated with an increased risk of AMD, corrected for potential confounders (Odds Ratio (OR) 1.21 per 1mmol/L increase (95% confidence interval[CI] 1.14-1.29); while triglycerides were associated with a decreased risk (OR 0.94 per 1mmol/L increase [95%CI 0.91-0.97]). Both were associated with drusen size, higher HDL raises the odds of larger drusen while higher triglycerides decreases the odds. LDL-cholesterol only reached statistical significance in the association with early AMD (p=0.045). Regarding lipid sub fractions: the concentration of extra-large HDL particles showed the most prominent association with AMD (OR 1.24 [95%CI 1.10-1.40]). The CETP risk variant (rs17231506) for AMD was in line with increased-HDL levels (p=7.7x10-7); but LIPC risk variants (rs2043085, rs2070895) were associated in an opposite way (p=1.0x10-6 and 1.6x10-4). Conclusions: Our study suggests that HDL-cholesterol is associated with increased risk of AMD and triglycerides negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL sub fractions seem to be drivers in the relation with AMD, variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains a question to be answered.