title: Can genetic associations change with age? CFH and age-related macular degeneration.
abstract: Genetic variation in the gene encoding complement factor H (CFH) on chromosome 1q31 has repeatedly been associated with an increased risk of age-related macular degeneration (AMD); however, previous studies have had inadequate numbers of participants across a sufficiently wide age range to determine whether the association varies by age. We conducted a genetic case-control study using data from 2294 cases and 2294 controls selected from the Melbourne Collaborative Cohort Study, matched on age, sex and region of origin. Four consistently replicated CFH single-nucleotide polymorphisms (SNPs) were genotyped: rs1061170 (Y402H), rs2274700, rs393955 and rs800292; their relationship with AMD prevalence was determined across the age range 48-86. A difference in genotype frequencies was seen across age groups, where the low-risk homozygote prevalence rose with each increasing age group. Associations with early AMD were strongly modified by age for three of the four SNPs (interaction P-value: 0.01-0.00003). An inverse association between the high-risk homozygote for each SNP and early AMD was observed in the younger age groups [odds ratios (OR) range 0.37-0.48 for age <55], reversing to a positive association with increasing age (OR 1.87-2.8 for age >75). The direction of associations for this gene change was from inverse to risk with increasing age. These findings have important implications for predictive models for AMD and potentially other age-related diseases which extrapolate risks from older cohorts, as they assume homogeneity of association by age, which might not exist.
authors.affiliation: Centre for Eye Research Australia, University of Melbourne/Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia. madeleine.adams@bigpond.com
authors.forename: Madeleine K M
authors.initials: MK
authors.lastname: Adams
authors.forename: Julie A
authors.initials: JA
authors.lastname: Simpson
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Richardson
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Guymer
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Williamson
authors.forename: Stuart
authors.initials: S
authors.lastname: Cantsilieris
authors.forename: Dallas R
authors.initials: DR
authors.lastname: English
authors.forename: Khin Zaw
authors.initials: KZ
authors.lastname: Aung
authors.forename: Galina A
authors.initials: GA
authors.lastname: Makeyeva
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: John
authors.initials: J
authors.lastname: Hopper
authors.forename: Liubov D
authors.initials: LD
authors.lastname: Robman
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D017242:Complement Factor H / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio
chemical_list: D017242:Complement Factor H