Can genetic associations change with age? CFH and age-related macular degeneration.

Adams, M.K. ; Simpson, J.A. ; Richardson, A.J. ; Guymer, R.H. ; Williamson, E. ; Cantsilieris, S. ; English, D.R. ; Aung, K.Z. ; Makeyeva, G.A. ; Giles, G.G. ; Hopper, J. ; Robman, L.D. ; Baird, P.N. ;
Can genetic associations change with age? CFH and age-related macular degeneration.
Hum Mol Genet, 2012; 21(23):5229-36

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.