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 the most common form of irreversible blindness in developed countries 1,2 . Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD [3][4][5][6][7][8] . Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histo-compatibility complex class III region, for genetic variation in two independent cohorts comprising ~900 individuals with AMD and ~400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0. 45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.Correspondence should be addressed to R.A. (rla22@columbia.edu) or M.D. (dean@ncifcrf.gov). Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTION STATEMENTThe AMD Genetics Clinical Study Group includes Stanley Chang, Lawrence A. Yannuzzi, John C. Merriam and Irene Barbazetto (Department of Ophthalmology, Columbia University, New York); Leonid E. Lerner (F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia) and Stephen Russell, Jamal Hoballah, Jill Hageman and Heather Stockman (Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa, USA). COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Genetics website for details).Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Inflammation has a central role in the pathobiology of AMD 9-14 . Dysfunction of the complement pathway is proposed to induce significant damage to macular cells, leading to atrophy, degeneration and the elaboration of choroidal neovascular membranes 3,[15][16][17] . Activation of the alternative pathway is initiated by cleavage of C3b-bound factor B (BF), resulting in the formation of the C3Bb complex (C3 convertase). This complex is stabilized by properdin, whereas its dissociation is accelerated by regulatory proteins, including complement factor H (CFH), the major inhibitor of the alternative complement pathway. As CFH haplotypes are associated with AMD 3 , we hypothesized that the same may be true for activators of the same pathway, such as complement factor B (BF). BF and compl...

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.

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/ Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.A ge-related macular degeneration (AMD) is a common, lateonset neurodegenerative disorder that is modified by covariates including smoking and body mass index, and it has a 3-to 6-fold higher recurrence ratio in siblings than in the general population (1). The burden of AMD is increasing among the growing elderly population. The advanced form of AMD is clinically significant, and it causes visual loss and reduces quality of life.