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

In-Place Augmented Reality

In this paper we present a new vision-based approach for transmitting virtual models for Augmented Reality (AR). A two dimensional representation of the virtual models is embedded in a printed image. We apply image-processing techniques to interpret the printed image and extract the virtual models, which are then overlaid back on the printed image. The main advantages of our approach are: (1) the image of the embedded virtual models and their behaviors are understandable to a human without using an AR system, and (2) no database or network communication is required to retrieve the models. The latter is useful in scenarios with large numbers of users. We implemented an AR system that demonstrates the feasibility of our approach. Applications in education, advertisement, gaming, and other domains can benefit from our approach, since content providers need only to publish the printed content and all virtual information arrives with it

In-Place Sketching for content authoring in Augmented Reality games

Sketching leverages human skills for various purposes. In-Place Augmented Reality Sketching experiences build on the intuitiveness and flexibility of hand sketching for tasks like content creation. In this paper we explore the design space of In-Place Augmented Reality Sketching, with particular attention to content authoring in games. We propose a contextual model that offers a framework for the exploration of this design space by the research community. We describe a sketch-based AR racing game we developed to demonstrate the proposed model. The game is developed on top of our shape recognition and 3D registration library for mobile AR

Genome wide association study and genomic risk prediction of age related macular degeneration in Israel.

The risk of developing age-related macular degeneration (AMD) is influenced by genetic background. In 2016, the International AMD Genomics Consortium (IAMDGC) identified 52 risk variants in 34 loci, and a polygenic risk score (PRS) from these variants was associated with AMD. The Israeli population has a unique genetic composition: Ashkenazi Jewish (AJ), Jewish non-Ashkenazi, and Arab sub-populations. We aimed to perform a genome-wide association study (GWAS) for AMD in Israel, and to evaluate PRSs for AMD. Our discovery set recruited 403 AMD patients and 256 controls at Hadassah Medical Center. We genotyped individuals via custom exome chip. We imputed non-typed variants using cosmopolitan and AJ reference panels. We recruited additional 155 cases and 69 controls for validation. To evaluate predictive power of PRSs for AMD, we used IAMDGC summary-statistics excluding our study and developed PRSs via clumping/thresholding or LDpred2. In our discovery set, 31/34 loci reported by IAMDGC were AMD-associated (P < 0.05). Of those, all effects were directionally consistent with IAMDGC and 11 loci had a P-value under Bonferroni-corrected threshold (0.05/34 = 0.0015). At a 5 × 10-5 threshold, we discovered four suggestive associations in FAM189A1, IGDCC4, C7orf50, and CNTNAP4. Only the FAM189A1 variant was AMD-associated in the replication cohort after Bonferroni-correction. A prediction model including LDpred2-based PRS + covariates had an AUC of 0.82 (95% CI 0.79-0.85) and performed better than covariates-only model (P = 5.1 × 10-9). Therefore, previously reported AMD-associated loci were nominally associated with AMD in Israel. A PRS developed based on a large international study is predictive in Israeli populations

Impaired Cholesterol Efflux in Senescent Macrophages Promotes Age-Related Macular Degeneration

Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases. [Display omitted] ► Macrophage senescence impairs cholesterol efflux and promotes macular degeneration ► Senescent macrophages polarize to a proangiogenic, disease-promoting phenotype ► Macrophage cholesterol efflux is regulated by miR33 and its target ABCA1 ► Age-related decrease in macrophage cholesterol efflux is therapeutically reversibl