Genetic analysis of age-related macular degeneration highlights precision therapy opportunities for patients with high polygenic risk

Importance: In the past two decades, genetic studies have elucidated the contributions of key biological pathways to the pathogenesis of age-related macular degeneration (AMD), including the predominant role of complement. Yet, clinical treatment of AMD with complement inhibitors has met with limited success. Objectives: To examine whether genetic heterogeneity in complement pathway activity, as represented by a polygenic risk score (PRS), may account for genetically predicted differential response to therapy with complement inhibitors in AMD. We additionally explored this effect on quantitative biomarkers of disease derived from optical coherence tomography (OCT). Subjects: Participants were ascertained from four large-scale cohorts (UK Biobank, eMERGE, International Age-related Macular Degeneration Genomics Consortium (IAMDGC), Mass General Brigham Biobank) spanning 30,251 AMD cases and 438,016 AMD controls. Methods: Using the available genomic data, we identified functional variants in C3 and CFB to serve as proxies for complement inhibitor drug effects, generated a pharmacomimetic score for each drug target, and tested each score for interaction with genome-wide and complement pathway-specific AMD polygenic risk scores (PRS). In each cohort, subjects were divided into low, medium, and high AMD risk groups based on quantiles of the PRS, such that each risk group included one-third of the cohort's AMD cases. Drug target variant associations with AMD were evaluated in each risk group, as well as in all-comers. Quantitative biomarker analysis leveraging retinal phenotypes derived from optical coherence tomography (OCT) data was also performed. Main Outcome Measures: AMD case status and OCT-derived measures of retinal thickness Results: Among AMD cases, mean age at diagnosis ranged 76-80 years and 40-48% were male across the four cohorts. Functional genetic variants serving as proxies for C3 and CFB inhibition had an effect on AMD risk that was 1.6 to 2.3 times higher in the high complement pathway-specific PRS group compared to all-comers. Interactions between pharmacomimetic scores and the PRS were statistically significant, with replication across cohorts. Statistical support was strongest in three cohorts for C3 and across all four cohorts for CFB. Examining retinal thickness phenotypes (eg. ISOS-RPE), genetic drug proxy by PRS interaction was nominally significant for CFB, and directionally consistent for C3. Our results point to a continuous relationship between genetic complement activation/inhibition and AMD risk, across disease stages, without threshold effects. Conclusions: Our findings suggest that patient heterogeneity due to genetically-influenced complement activation may explain the limited efficacy of AMD treatment with complement inhibitors to date. Prospective studies are warranted to assess whether precision therapy with complement inhibitors may be achieved by enrichment of patients with high PRS in future trials.