title: Rare complement factor H variant associated with age-related macular degeneration in the Amish.
abstract: OBJECTIVE
  Age-related macular degeneration is the leading cause of blindness among the adult population in the developed world. To further the understanding of this disease, we have studied the genetically isolated Amish population of Ohio and Indiana.
  
  
  METHODS
  Cumulative genetic risk scores were calculated using the 19 known allelic associations. Exome sequencing was performed in three members of a small Amish family with AMD who lacked the common risk alleles in complement factor H (CFH) and ARMS2/HTRA1. Follow-up genotyping and association analysis was performed in a cohort of 973 Amish individuals, including 95 with self-reported AMD.
  
  
  RESULTS
  The cumulative genetic risk score analysis generated a mean genetic risk score of 1.12 (95% confidence interval [CI]: 1.10, 1.13) in the Amish controls and 1.18 (95% CI: 1.13, 1.22) in the Amish cases. This mean difference in genetic risk scores is statistically significant (P = 0.0042). Exome sequencing identified a rare variant (P503A) in CFH. Association analysis in the remainder of the Amish sample revealed that the P503A variant is significantly associated with AMD (P = 9.27 × 10(-13)). Variant P503A was absent when evaluated in a cohort of 791 elderly non-Amish controls, and 1456 non-Amish cases.
  
  
  CONCLUSIONS
  Data from the cumulative genetic risk score analysis suggests that the variants reported by the AMDGene consortium account for a smaller genetic burden of disease in the Amish compared with the non-Amish Caucasian population. Using exome sequencing data, we identified a novel missense mutation that is shared among a densely affected nuclear Amish family and located in a gene that has been previously implicated in AMD risk.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hoffman
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Cooke Bailey
authors.affiliation: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: D'Aoust
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: William
authors.initials: W
authors.lastname: Cade
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: Juan
authors.initials: J
authors.lastname: Ayala-Haedo
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Fuzzell
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Laux
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: Larry D
authors.initials: LD
authors.lastname: Adams
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: Lori
authors.initials: L
authors.lastname: Reinhart-Mercer
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Caywood
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: Patrice
authors.initials: P
authors.lastname: Whitehead-Gay
authors.affiliation: Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, Tennessee, United States.
authors.forename: Anita
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Wang
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061365:Amish / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007196:Indiana; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D009820:Ohio; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: C493495:CFH protein, human; D017242:Complement Factor H
keywords: age-related macular degeneration; exome sequencing; linkage analysis; rare variant; risk score analysis