OBJECTIVE: To identify genetic determinants specific to reticular pseudodrusen (RPD) compared with drusen. DESIGN: Genome-wide association study (GWAS) SUBJECTS: Participants with RPD, drusen, and controls from the UK Biobank (UKBB), a large, multisite, community-based cohort. METHODS: A deep learning framework analyzed 169,370 optical coherence tomography (OCT) volumes to identify cases and controls within the UKBB. Five retina specialists validated the cohorts using OCT and color fundus photographs. Several GWAS were undertaken utilizing the quantity and presence of RPD and drusen. Genome-wide significance was defined as p<
5e-8. MAIN OUTCOMES MEASURES: Genetic associations were examined with the number of RPD and drusen within 'pure' cases, where only RPD or drusen were present in either eye. A candidate approach assessed 46 previously known AMD loci. Secondary GWAS were conducted for number of RPD and drusen in mixed cases, and binary case-control analyses for pure RPD and pure drusen. RESULTS: The study included 1,787 participants: 1,037 controls, 361 pure drusen, 66 pure RPD, and 323 mixed cases. The primary pure RPD GWAS identified four genome-wide significant loci: rs11200630 near ARMS2-HTRA1 (p=1.9e-09), rs79641866 at PARD3B (p=1.3e-08), rs143184903 near ITPR1 (p=8.1e-09), and rs76377757 near SLN (p=4.3e-08). The latter three are uncommon variants (minor allele frequency <
5%). A significant association at the CFH locus was also observed using a candidate approach (p=1.8e-04). For pure drusen, two loci reached genome-wide significance: rs10801555 at CFH (p=6.0e-33) and rs61871744 at ARMS2-HTRA1 (p=4.2e-20). CONCLUSIONS: The study highlights a clear association between the ARMS2-HTRA1 locus and higher RPD load. Although the CFH locus association did not achieve genome-wide significance, a suggestive link was observed. Three novel associations unique to RPD were identified, albeit for uncommon genetic variants. Further studies with larger sample sizes are needed to explore these findings.