Fig. 2: Genetic modulators of FHR-4 levels in plasma, RPE/Bruch’s membrane/choroid, and vitreous humor.

a Graph showing the AMD odds ratios (OR), generated using the IAMDGC cohort (13,378 controls and 17,541 cases, see also Supplementary Tables 3 and 4), of quantitative trait loci (QTLs) identified through expression QTL (rs1410996, rs7531555) or protein QTL (rs61818956, rs10494745, rs7531555) analyses as a function of location on chromosome 1. The major/minor alleles and effect of the minor alleles on FHR-4 variation are also shown. Independent QTLs, highlighted in red, were identified through haplotype analyses performed using 1000 Genomes Project phase 3 (1000 G EUR) subjects (shown in the panel) and controls from the Utah & Iowa and IAMDGC cohorts (Supplementary Fig. 9). b Box plots of log-transformed and centered plasma FHR-4 levels by rs1410996 (IAMDGC 1.1) and rs7531555 genotypes (404 independent biological samples). Analyses of genetic combinations indicate that the expression QTL effect associated with rs1410996 is entirely attributable to rs7531555. c Box plot showing the distribution of log-transformed and centered plasma FHR-4 levels by rs61818956, rs10494745, and rs7531555 genotypes (486 independent biological samples). d FHR-4 immunohistochemistry in retinal pigment epithelium (RPE)/Bruch’s membrane/choroid tissues from an eye donor obtained using anti-FHR-4 antibody and warp red chromagen shows intense staining in Bruch’s membrane (BM) and between pillars of the choriocapillaris (CC). An image of a negative control can be found in Supplementary Fig. 12. e Variations in log-transformed and centered FHR-4 levels measured in RPE/Bruch’s membrane/choroid and vitreous lysates with the three independent rs61818956, rs10494745, and rs7531555 genotypes (229 independent biological samples, see Supplementary Table 6). The directional effect of QTLs in ocular samples is consistent with that observed in plasma samples. In b, c, and e, in all box plots the horizontal center lines correspond to the medians of the log-transformed and centered FHR-4 distribution and the boxes delineate the 25th/75th percentile. The vertical solid lines represent the full range of the log-transformed and centered FHR-4 distribution in each group. Dots beyond this line indicate potential outliers. Associations with log-transformed and centered FHR-4 levels were assessed using the Kruskal–Wallis test. Post-hoc pairwise comparisons were performed using the Conover–Iman test. All p-values are two-sided and adjusted for multiple testing using Bonferroni corrections. Source data for these plots are provided as a Source Data file.