title: Distinct Genetic Risk Profile of the Rapidly Progressing Diffuse-Trickling Subtype of Geographic Atrophy in Age-Related Macular Degeneration (AMD).
abstract: To genetically characterize a subphenotype of geographic atrophy (GA) in AMD associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence imaging.
  
  
  
  Patients from the Fundus Autofluorescence in Age-Related Macular Degeneration Study were phenotyped for diffuse-trickling GA (dt-GA; n = 44). DNA was analyzed for 10 known AMD-associated genetic variants. A genetic risk score (GRS) was calculated and compared with patients with nondiffuse-trickling GA (ndt-GA; n = 311) and individuals from the 1000 genomes project (1000G; n = 267). Given the phenotypic overlap between diffuse-trickling and late-onset retinal degeneration (LORD), all C1QTNF5 exons and their exon/intron boundaries were sequenced.
  
  
  
  A statistically significant difference in allele frequencies between dt-GA and ndt-GA were found for CFH:rs1061170 and CFH:rs800292 (Pcorrected = 0.03). The ARMS2 variant rs10490924 was significantly more frequent in dt-GA than in 1000G individuals (Pcorrected < 0.01). The GRS of dt-GA patients was in-between the score of the 1000G individuals and that of patients with ndt-GA, significantly differing from both (Pcorrected <0.01). Sequencing of C1QTNF5 revealed 28 unique variants although none showed a statistically significant association with dt-GA when compared with 1000G individuals.
  
  
  
  The dt-GA phenotype shows a remarkably different genetic risk profile from other GA phenotypes secondary to AMD. Disease-associated C1QTNF5 mutations were not identified. Together, these results suggest that the dt-GA phenotype is associated with a genetic background substantially different from other GA phenotypes and underlines the necessity to refine the clinical phenotyping, specifically when aiming for individualized therapies in AMD.
authors.affiliation: Department of Ophthalmology University of Bonn, Bonn, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Fleckenstein
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Grassmann
authors.affiliation: Department of Ophthalmology University of Bonn, Bonn, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Department of Ophthalmology University of Bonn, Bonn, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Pfau
authors.affiliation: Department of Ophthalmology University of Bonn, Bonn, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Czauderna
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strunz
authors.affiliation: Eye Center Southwest, Stuttgart-Vaihingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: von Strachwitz
authors.affiliation: Department of Ophthalmology University of Bonn, Bonn, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitz-Valckenberg
authors.affiliation: Department of Ophthalmology University of Bonn, Bonn, Germany.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Holz
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
mesh_terms: D000368:Aged; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005787:Gene Frequency; D005838:Genotype; D057092:Geographic Atrophy / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008268:Macular Degeneration / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D041623:Tomography, Optical Coherence
chemical_list: C487851:C1QTNF5 protein, human; D003094:Collagen; D004247:DNA