Genetic Distinctions Between Reticular Pseudodrusen and Drusen: Insights from a Genome-Wide Association Study
Authors: Schwartz Roy , Warwick Alasdair N. , Khawaja Anthony P. , Luben Robert , Khalid Hagar , Phatak Sumita , Jhingan Mahima , de Vente Coen , Valmaggia Philippe , Liakopoulos Sandra , Olvera-Barrios Abraham , Sánchez Clara I. , Egan Catherine , Bonelli Roberto , Tufail Adnan 
Published: September 2024

Purpose

To explore genetic determinants specific to reticular pseudodrusen (RPD), and to compare these with genetic associations for drusen.

Setting

Participants with RPD, drusen, or controls from the UK Biobank (UKBB), a large, multisite, community-based cohort study.

Methods

A previously validated deep learning framework was deployed on 169,370 optical coherence tomography (OCT) volumes from the UKBB to identify cases with RPD and/or drusen and controls without these phenotypes. Cases were included if they were 60 years or older, with at least 5 lesions. Five retina specialists manually validated the cohorts using OCT and color fundus photographs. Quantifications of RPD and drusen derived by the framework were used as variables. Two primary genome-wide association study (GWAS) analyses were performed to explore potential genetic associations with number of RPD and drusen within ‘pure’ cases, where only RPD or drusen were present in either eye. A candidate approach was furthermore adopted to assess 46 previously known AMD loci. Secondary GWAS were undertaken for number of RPD and drusen in mixed cases, as well as binary case-control analyses for pure RPD and pure drusen. Genome-wide significance was defined as p<5e-8.

Results

A total of 1,787 participants were identified and analysed, including 1,037 controls, 361 pure drusen, 66 pure RPD and 323 mixed cases. The primary pure RPD GWAS yielded four genome-wide significant loci: rs11200630/ARMS2-HTRA1(p=1.9e-09), rs79641866/PARD3Bon chromosome 2 (p=1.3e-08), rs143184903/ITPR1on chromosome 3 (p=8.1e-09), and rs76377757/SLNon chromosome 11 (p=4.3e-08). The latter three are all uncommon variants (minor allele frequency <5%). A significant association atCFHwas also observed adopting a candidate approach (p=1.8e-04).

Two loci reached genome-wide significance for the primary pure drusen GWAS: rs10801555/CFHon chromosome 1 (p=6.0e-33) and rs61871744/ARMS2-HTRA1on chromosome 10 (p=4.2e-20). For the mixed RPD and drusen secondary analyses, lead variants at both theCFHandARMS2-HTRA1loci reached genome-wide significance, withC2-CFB-SKIV2Ladditionally associated for mixed drusen alone. Findings from the binary case-control GWAS for drusen mirrored those of the primary drusen analysis, however no variants reached genome-wide significance in the case-control RPD GWAS.

Conclusions

Our findings indicate a clear association between theARMS2-HTRA1locus with higher RPD load. Although the association at theCFHlocus did not reach genome-wide significance, we observed a suggestive link. We furthermore identified three novel associations that are unique to RPD, albeit for uncommon genetic variants. These findings were only observable when quantifying RPD load as a continuous trait, which increased the study’s statistical power. Further studies with larger sample sizes are now required to explore the relative contributions ofAMRS2-HTRA1andCFHto RPD development, and to explore the validity of these newly presented RPD-specific genetic associations.