title: (Epi)Genetic analyses of age-related macular degeneration: case-control and discordant twin studies.
abstract: OBJECTIVE
  Phenotypic discordance in monozygotic (MZ) twin pairs can have an epigenetic or genetic basis. Although age-related macular degeneration (AMD) has a strong genetic component, few studies have addressed its epigenetic basis.
  
  
  METHODS
  Using SNP arrays, we evaluated differences in copy number variation (CNV) and allele-specific methylation (ASM) patterns (via methyl-sensitive restriction enzyme digestion of DNA) in MZ twin pairs from the US Twin Study of AMD. Further analyses examined the relationship between ASM and CNVs with AMD by both case/control analysis of ASM at candidate regions and by analysis of ASM and CNVs in twins discordant for AMD.
  
  
  RESULTS
  The frequency of ASM sites differs between cases and controls in regions surrounding the AMD candidate genes CFH, C2 and CFB. While ASM patterns show a substantial dependence on local sequence polymorphisms, we observed dissimilar patterns of ASM between MZ twins. The genes closest to the sites where discordant MZ twins have dissimilar patterns of ASM are enriched for genes implicated in gliosis, a process associated with neovascular AMD. Similar twin-based analyses revealed no AMD-associated CNVs.
  
  
  CONCLUSIONS
  Our results provide evidence of epigenetic influences beyond the known genetic susceptibility and implicate inflammatory responses and gliosis in the etiology of AMD.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Mass., USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Hutchinson
authors.forename: Jes
authors.initials: J
authors.lastname: Fagerness
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.forename: Robyn
authors.initials: R
authors.lastname: Reynolds
authors.forename: Alex
authors.initials: A
authors.lastname: Zak
authors.forename: Alexander
authors.initials: A
authors.lastname: Gimelbrant
authors.forename: Robert
authors.initials: R
authors.lastname: Plenge
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.forename: Andrew
authors.initials: A
authors.lastname: Chess
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D057890:Epigenomics; D005911:Gliosis / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008268:Macular Degeneration / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014430:Twins, Monozygotic / Q000235:genetics*; D014481:United States / Q000453:epidemiology