Fig 1: Single-variant, haplotype, and diplotype association analyses performed to refine AMD associations within the CFH-CFHR5 extended region and to stratify human subjects and donor eyes by disease susceptibility, with associated functional effects.a Schematic of the factor H (FH), factor H-like 1 (FHL-1), and factor H-related (FHR) family of proteins showing short consensus repeats (SCR) numbered from the N-terminus and percent amino acid similarities. The location of amino acid changes associated with FH/FHL-1 Y402H and FH/FHL-1 I62V is highlighted, as is the result of the CFHR3/1 deletion. The schematic was minimally modified from Trends in Immunology, 36, Ózsi, M., Tortajada, A., Uzonyi, B., Goicoechea de Jorge, E. & Rodríguez de Córdoba, S., Factor H-related proteins determine complement-activating surfaces, 374–384, Copyright (2015), with permission from Elsevier84. In b displayed odds ratios (OR) were generated using the IAMDGC cohort (13,378 controls and 17,541 cases, see also Supplementary Table 2). Additional variant labels, major/minor alleles, and direction of effect on AMD susceptibility are also provided. c The combination of function-altering FH/FHL-1 Y402H and FH/FHL-1 I62V variants and the presence or absence of the CFHR3/1 deletion yields four common haplotypes, with AMD associations ranging from protection to neutrality and risk. Odds ratios, confidence intervals (CI), and p-values (two-sided) were obtained using logistic regressions including AMD case/control status as the dependent variable and age, sex, and the first two genetic principal components for the IAMDGC cohort as covariates. Bonferroni correction for multiple testing of four haplotypes = 0.0125 (0.05/4). d Odds ratios and 95% CI for combinations of the four common haplotypes, generated independently with the IAMDGC (13,378 controls and 17,541 cases) and Utah & Iowa (1587 controls and 3200 cases) cohorts, reveal an AMD susceptibility continuum, with protective haplotypes mitigating risk haplotypes in a one-to-one manner. Odds ratios, 95% CI, and p-values (two-sided) were obtained using logistic regressions including AMD case/control status as the dependent variable and age, sex, and the first two genetic principal components for the IAMDGC cohort as covariates. Bonferroni correction for multiple testing of ten diplotypes = 0.005 (0.05/10).