Genome-Wide Association Identifies SKIV2L and MYRIP as Protective Factors for Age-Related Macular Degeneration

Publication Type
Journal Article
Year of Publication
Kopplin, L; Igo Jr., R; Wang, Y; Sivakumaran, T; Hagstrom, S; Peachey, N; Francis, P; Klein, M; Sangiovanni, J; Chew, E; Pauer, G; Sturgill, G; Joshi, T; Tian, L; Xi, Q; Henning, A; Lee, K; Klein, R; Klein, B; Iyengar, S
Genes Immun
Start Page
Date Published
80 and over; Adult; Aged; Alleles; Complement Factor H/genetics*; DNA Helicases/genetics*; Genome-Wide Association Study; Genotype; Humans; Macular Degeneration/genetics*; Middle Aged; Polymorphism; Proteins/genetics; Single Nucleotide
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. We conducted a genome-wide association study in a series of families enriched for AMD and completed a meta-analysis of this new data with results from reanalysis of an existing study of a late-stage case-control cohort. We tested the top findings for replication in 1896 cases and 1866 controls and identified two novel genetic protective factors for AMD. In addition to the complement factor H (CFH) (P=2.3 × 10(-64)) and age-related maculopathy susceptibility 2 (ARMS2) (P=1.2 × 10(-60)) loci, we observed a protective effect at rs429608, an intronic SNP in SKIV2L (P=5.3 × 10(-15)), a gene near the complement component 2 (C2)/complement factor B (BF) locus, that indicates the protective effect may be mediated by variants other than the C2/BF variants previously studied. Haplotype analysis at this locus identified three protective haplotypes defined by the rs429608 protective allele. We also identified a new potentially protective effect at rs2679798 in MYRIP (P=2.9 × 10(-4)), a gene involved in retinal pigment epithelium melanosome trafficking. Interestingly, MYRIP was initially identified in the family-based scan and was confirmed in the case-control set. From these efforts, we report the identification of two novel protective factors for AMD and confirm the previously known associations at CFH, ARMS2 and C3