Abstract
Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15–65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2–136; P = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0–25; P = 0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.
Highlights
Age-related macular degeneration (AMD, MIM 603075) is a retinal disorder that causes progressive visual impairment in individuals aged over 50 years [1]
To investigate the involvement of rare variants in the component 3 (C3) gene in AMD, the exons and flanking introns of C3 were sequenced in a discovery cohort of 84 AMD cases (Table 1) from the Nijmegen area, the Netherlands
The Lys155Gln variant, which has recently been associated with AMD [10,11,12], was found in five cases, while variants Arg735Trp and Ser1619Arg were found in one case each
Summary
Age-related macular degeneration (AMD, MIM 603075) is a retinal disorder that causes progressive visual impairment in individuals aged over 50 years [1]. GWASs identified common variants at 19 loci that influence disease susceptibility, accounting for 15–65% of the heritability [3,4]. It has been hypothesized that the remaining genetic fraction influencing the risk for development of AMD, the so-called missing heritability, may be explained by rare, highly penetrant variants [4]. Simulation studies suggested that common variants are insufficient to account for disease burden in densely affected AMD families and that rare penetrant variants would offer a likely explanation [5]. Rare, highly penetrant variants in the genes encoding complement factor H (CFH), complement factor I (CFI), complement component 3 (C3) and complement component 9 (C9) have recently been found to be associated with AMD [8,9,10,11,12]
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