Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration

Abstract

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 1 896 cases and 1 866 controls and identified two novel genetic protective factors for AMD. In addition to the CFH (p=2.3×10−64) and 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 C2/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.

Age-related macular degeneration and the complement system

“…Maller et al 2006), (Spencer et al 2007;Seddon et al 2009;Francis et al 2009) Unknown whether these SNPs are associated with AMD due to a functional change in either the C2 or CFB genes, or even both. rs547154 (C2) None (SNP in non-coding region) Maller et al 2006), (Spencer et al 2007;Jakobsdottir et al 2008;Richardson et al 2009;Gibson et al 2010) NB: rs9332739 (C2) in LD with rs4151667 (CFB), and rs547154 (C2) in LD with rs641153 (CFB) rs4151667 (CFB) L9H Maller et al 2006) rs641153 (CFB) R32Q Maller et al 2006), (Spencer et al 2007;Seddon et al 2009;Richardson et al 2009;Kopplin et al 2010) C3 19p13.3-p13.2 rs2230199 R102G (Yates et al 2007;Maller et al 2007;Spencer et al 2008b;Seddon et al 2009;Despriet et al 2009;Park et al 2009;Francis et al 2009;Scholl et al 2009;Chen et al 2010;McKay et al 2010;Gibson et al 2010;Kopplin et al 2010) NB. These two SNPs are in LD with each other rs1047286 P314L (Spencer et al 2008b;Despriet et al 2009;Park et al 2009; …”

“…An intronic variation in a near-by gene, SuperkillerViralicidic Activity 2 (SKIV2L) has also been associated with AMD. This gene is considered to have a role in defence against RNA viruses; however its association with complement is uncertain Kopplin et al 2010).…”

A Genetic Variant in theSKIV2LGene Is Significantly Associated With Age-Related Macular Degeneration in a Han Chinese Population

“…They concluded that variations within SKIV2L might exert a functional effect in AMD. Furthermore, Kopplin et al 34 performed a genome-wide association study (GWAS) in 1896 cases of AMD and 1866 controls and observed a protective effect of an intronic SNP, rs429608 (P ¼ 5.3 3 10 À15 ), to AMD in the SKIV2L gene. In addition, Lee et al 40 and Kondo et al 41 investigated the association between the C2/BF locus and PCV, which is one type of wet AMD (wet AMD includes CNV and PCV); they could not find a significant association between the previously reported SNPs and PCV in Singapore Chinese and Japanese individuals.…”

“…Six of these 13 SNPS, including rs9332739, rs547154, rs4151667, rs641153, rs760070, and rs429608, were reported in previous studies to be associated with AMD. 24,33,34 The other seven haplotypetagging SNPs were obtained from the C2-BF-RD RNA-binding protein (RDBP)-SKIV2L-serine/threonine kinase 19 (STK19) region spanning 46 kb (Chr6: 32,001,000-32,047,000) in the Han Chinese population in Beijing, China (CHB), drawn from the HapMap database (HapMap Public Release #27 on Genome Browser, http://hapmap.ncbi.nlm.nih.gov/). Several of these SNPs had been genotyped in some of the samples in our previous study.…”

“…[24][25][26][27][28] However, the results of the association studies between genetic variants in the C2/BF and C3 genes and AMD in East Asian populations, including Korean, Chinese, Japanese, and so on, were inconsistent. [29][30][31][32] Yanagisawa et al 32 recently identified that a different SNP in the C3 gene, rs2241394, showed significant association with wet AMD in Japanese populations.In addition, recent studies have indicated that genetic variants in the C2/BF neighboring gene, superkiller viralicidic activity 2-like (SKIV2L), show significant association with AMD in Caucasians, 33,34 suggesting that the SKIV2L gene is a strong candidate for AMD at this locus. In this study, we investigated if genetic variants of the SKIV2L gene are significantly associated with AMD in a Han Chinese population.…”