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.

In age-related macular degeneration (AMD), rare variants in the complement system have been described, but their functional consequences remain largely unexplored. OBJECTIVES To identify new rare variants in complement genes and determine the functional effect of identified variants on complement levels and complement regulation in serum samples from carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS This study evaluated affected (n = 114) and unaffected (n = 60) members of 22 families with AMD and a case-control cohort consisting of 1831 unrelated patients with AMD and 1367 control individuals from the European Genetic Database from March 29, 2006, to April 26, 2013, in Nijmegen, the Netherlands, and Cologne, Germany. Exome sequencing data of families were filtered for rare variants in the complement factor H (CFH), complement factor I (CFI), complement C9 (C9), and complement C3 (C3) genes. The case-control cohort was genotyped with allele-specific assays. Serum samples were obtained from carriers of identified variants (n = 177) and age-matched noncarriers (n = 157). Serum concentrations of factor H (FH), factor I (FI), C9, and C3 were measured, and C3b degradation ability was determined. MAIN OUTCOMES AND MEASURES Association of rare variants in the CFH, CFI, C9, and C3 genes with AMD, serum levels of corresponding proteins, and C3b degradation ability of CFH and CFI variant carriers. RESULTS The 1831 unrelated patients with AMD had a mean (SD) age of 75.0 (9.4) years, and 60.5% were female. The 1367 unrelated control participants had a mean (SD) age of 70.4 (7.0), and 58.7% were female. All individuals were of European descent. Rare variants in CFH, CFI, C9, and C3 contributed to an increased risk of developing AMD (odds ratio, 2.04; 95% CI, 1.47-2.82; P < .001). CFI carriers had decreased median FI serum levels (18.2 μg/mL in Gly119Arg carriers and 16.2 μg/mL in Leu131Arg carriers vs 27.2 and 30.4 μg/mL in noncarrier cases and controls, respectively; both P < .001). Elevated C9 levels were observed in Pro167Ser carriers (10.7 μg/mL vs 6.6 and 6.1 μg/mL in noncarrier cases and controls, respectively; P < .001). The median FH serum levels were 299.4 μg/mL for CFH Arg175Gln and 266.3 μg/mL for CFH Ser193Leu carriers vs 302.4 and 283.0 μg/mL for noncarrier cases and controls, respectively. The median C3 serum levels were 943.2 μg/mL for C3 Arg161Trp and 946.7 μg/mL for C3 Lys155Gln carriers vs 874.0 and 946.7 μg/mL for noncarrier cases and controls, respectively. The FH and FI levels correlated with C3b degradation in noncarriers (R 2 = 0.35 and R 2 = 0.31, respectively; both P < .001). CONCLUSIONS AND RELEVANCE Reduced serum levels were associated with C3b degradation in carriers of CFI but not CFH variants, suggesting that CFH variants affect functional activity of FH rather than serum levels. Carriers of CFH (Arg175Gln and Ser193Leu) and CFI (Gly119Arg and Leu131Arg) variants have an impaired ability to regulate complement activation and may benefit more from complement-inhibiting therapy than patie...

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Sunlight exposure during working life is an important risk factor for AMD, whereas sunlight exposure after retirement seems to have less influence on the disease development. Therefore, preventive measures, for example, wearing sunglasses to minimize sunlight exposure, should start early to prevent development of AMD later in life.