Abstract
Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed GWAS using neovascular AMD cases in East Asian. The discovery stage compared 581,252 single nucleotide polymorphisms (SNPs) between 803 unilateral and 321 bilateral Japanese cases but no SNP showed genome-wide significance, while SNPs at six regions showed P-value < 1.0 × 10−5, STON1-GTF2A1L/LHCGR/FSHR, PLXNA1, CTNNA3, ARMS2/HTRA1, LHFP, and FLJ38725. The first replication study for these six regions comparing 36 bilateral and 132 unilateral Japanese cases confirmed significant associations of rs4482537 (STON1-GTF2A1L/LHCGR/FSHR), rs2284665 (ARMS2/HTRA1), and rs8002574 (LHFP) to bilaterality. In the second replication study comparing 24 bilateral and 78 unilateral cases from Singapore, rs4482537 (STON1-GTF2A1L/LHCGR/FSHR) only showed significant association. Meta-analysis of discovery and replication studies confirmed genome-wide level significant association (P = 2.61 × 10−9) of rs4482537 (STON1-GTF2A1L/LHCGR/FSHR) and strong associations (P = 5.76 × 10−7 and 9.73 × 10−7, respectively) of rs2284665 (ARMS2/HTRA1) and rs8002574 (LHFP). Our GWAS for neovascular AMD bilaterality found new genetic loci STON1-GTF2A1L/LHCGR/FSHR and confirmed the previously reported association of ARMS2/HTRA1.
Highlights
Complex disease caused by multiple environmental and genetic risk factors
Several studies reported that ARMS2/HTRA1 contributes to the bilaterality of late AMD10–16
Since most late Age-related macular degeneration (AMD) is neovascular AMD in East Asian and geographic atrophy is rare, we focused on only neovascular AMD
Summary
Complex disease caused by multiple environmental and genetic risk factors. Previous genome-wide association studies (GWASs) identified two major susceptibility loci for AMD; complement factor H (CFH) and age-related maculopathy susceptibility 2/high temperature requirement A1 (ARMS2/HTRA1). Several studies reported that ARMS2/HTRA1 contributes to the bilaterality of late AMD10–16. It is still controversial whether CFH increases the risk of AMD bilaterality[10, 12,13,14, 16,17,18,19]. To identify the genetic determinants associated with bilaterality of late AMD in East Asian, we conducted a GWAS comparing bilateral late AMD patients with unilateral late AMD patients. After finding genes associated with the bilaterality of neovascular AMD, we confirmed their susceptibility to AMD occurrence by comparing all neovascular AMD cases including both bilateral cases and unilateral cases with controls of Japanese general populations
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