title: A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene.
abstract: Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+].  Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated.  Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project.  Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.
authors.affiliation: Institute of Human Genetics and Department of Ophthalmology, University of Regensburg, Regensburg, Germany.
authors.forename: Lars G
authors.initials: LG
authors.lastname: Fritsche
authors.forename: Monika
authors.initials: M
authors.lastname: Fleckenstein
authors.forename: Britta S
authors.initials: BS
authors.lastname: Fiebig
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitz-Valckenberg
authors.forename: Almut
authors.initials: A
authors.lastname: Bindewald-Wittich
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Keilhauer
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Renner
authors.forename: Friederike
authors.initials: F
authors.lastname: Mackensen
authors.forename: Andreas
authors.initials: A
authors.lastname: Mößner
authors.forename: Daniel
authors.initials: D
authors.lastname: Pauleikhoff
authors.forename: Christine
authors.initials: C
authors.lastname: Adrion
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mansmann
authors.forename: Hendrik P N
authors.initials: HP
authors.lastname: Scholl
authors.forename: Frank G
authors.initials: FG
authors.lastname: Holz
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000080362:Stargardt Disease
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters