title: Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration†.
abstract: Although numerous common age-related macular degeneration (AMD) alleles have been discovered using genome-wide association studies, substantial disease heritability remains unexplained. We sought to identify additional common and rare variants associated with advanced AMD. A total of 4,332 cases and 25,268 controls of European ancestry from three different populations were genotyped using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants, and single variant and gene-based burden tests to identify rare variants. Two protective, low-frequency, non-synonymous variants were significantly associated with a decrease in AMD risk: A307V in PELI3 (odds ratio [OR] = 0.14, P = 4.3 × 10-10) and N1050Y in CFH (OR = 0.76, P = 6.2 × 10-12). The new variants have a large effect size, similar to some rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR = 18.82, P = 3.5 × 10-07), C3 K155Q (OR = 3.27, P = 1.5 × 10-10) and C9 P167S (OR = 2.04, P = 2.8 × 10-07). We also identified a strong protective signal for a common variant (rs8056814) near CTRB1 associated with a decrease in AMD risk (logistic regression: OR = 0.71, P = 1.8 × 10-07). Suggestive protective loci were identified in the COL4A3 and APOH genes. Our results support the involvement of common and low-frequency protective variants in this vision-threatening condition. This study expands the roles of the innate immune pathway as well as the extracellular matrix and high-density lipoprotein pathways in the aetiology of AMD.
authors.affiliation: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA.|Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Wagner
authors.affiliation: Hôpital Intercommunal, Hôpital Henri Mondor, Créteil Université Paris Est, Paris, France.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Souied
authors.affiliation: Helsinki University Eye Clinic, Helsinki, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Seitsonen
authors.affiliation: Helsinki University Eye Clinic, Helsinki, Finland.
authors.forename: Ilkka J
authors.initials: IJ
authors.lastname: Immonen
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Paavo
authors.initials: P
authors.lastname: Häppölä
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.|Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA.|Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.|Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.|Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.|Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA and.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA.|Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA.|Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
mesh_terms: D001324:Autoantigens; D016022:Case-Control Studies; D002918:Chymotrypsin / Q000235:genetics*; D024141:Collagen Type IV; D017242:Complement Factor H / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain; D017242:Complement Factor H; C503915:PELI3 protein, human; D044767:Ubiquitin-Protein Ligases; D002918:Chymotrypsin; C117609:chymotrypsin B