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Fifteen variants in 10q26 are in strong linkage disequilibrium and are associated with an increased risk for age-related macular degeneration (AMD), a frequent cause of blindness in developed countries. These variants tag a single-risk haplotype encompassing the genes  ARMS2  (age-related maculopathy susceptibility 2) and part of  HTRA1  (HtrA serine peptidase 1). To define the true AMD susceptibility gene in 10q26, several studies have focused on the influence of risk alleles on the expression of  ARMS2  and/or  HTRA1 , but the results have been inconsistent .  By heterologous expression of genomic  ARMS2  variants, we now show that  ARMS2  mRNA levels transcribed from the risk haplotype are significantly reduced compared with non-risk mRNA isoforms. Analyzing variant  ARMS2  constructs, this effect could specifically be assigned to the known insertion/deletion polymorphism (c.(*)372_815del443ins54) in the 3′-untranslated region of  ARMS2 . Reporter gene assays with  HTRA1  promoter sequences demonstrated the presence of a Müller glia-specific  cis -regulatory region further upstream of the transcription start site. However, AMD risk alleles had little or no effect on  HTRA1  promoter activity in the retina. Analysis of a large series of human  post-mortem  retina/retinal pigment epithelial samples heterozygous for the risk haplotype confirmed the  in vitro/ex vivo  results and demonstrated that the risk haplotype affects  ARMS2  but not  HTRA1  mRNA expression. Furthermore, we provide  in vivo  evidence that a common non-risk-associated non-synonymous variant (rs2736911) also leads to decreased  ARMS2  transcript levels. Consequently, our data suggest that pathogenic effects due to ARMS2 protein deficiency are unlikely to account for AMD pathology.

human molecular genetics

Risk- and non-risk-associated variants at the 10q26 AMD locus influence  ARMS2  mRNA expression but exclude pathogenic effects due to protein deficiency