Polygenic Risk Score and Rare Variant Burden Identified by Targeted Sequencing in a Group of Patients with Pigment Epithelial Detachment in Age-Related Macular Degeneration
Round 1
Reviewer 1 Report
General comments
The manuscript (ID: genes-2482546) submitted for consideration, titled ‘Polygenic risk score and rare variant burden identified by targeted sequencing in a group of patients with pigment epithelial detachment in age-related macular degeneration’, addressed the polygenetic risk score and rare variant burden from 334 patients and sub-grouped them into 47 patients manifesting PED (pigment epithelial detachment), in comparison to those with age-related macular degeneration without PED, and the healthy controls.
The authors managed to achieve the highest predictive value for a model consisting of six non-coding variants. Furthermore, the PED occurrence risk was found to be the highest in the first tercile, showing a 7.89-fold higher risk compared to the third tercile for AMD without PED, and a 7.22-fold higher risk compared to healthy controls. Although the rare variants burden was compared between the groups, no statistical significance was observed regarding the number of rare variants, predicted functional effect, and pathogenicity classification.
The manuscript is well-written with a novelty of PED complications in AMD, which has not been previously addressed. The materials and methods were solid for the study and the results are indicative as presented by polygenic risk scores. Particularly, the highest predictive value was achieved with six non-coding variants: rs760306 (BEST1), rs148662546 (BEST1), rs11569560 (C3), rs74600252 (GUCA1B), rs2240688 (PROM1) and rs185507582 (TCF4), and among them, TCF4 association with AMD and PED has not been reported.
The authors also indicated that PRS could have a potential for clinical utilities in risk stratification, early diagnosis, or even for planning personalized strategies. The non-significance of rare variants burden was interpreted as either due to small sample size or the rarity of variants. The limitation of only focusing on Polish patients and suggestions for future studies were also included in the discussion.
Overall, the manuscript has successfully addressed the PRS for PED complications in AMD and demonstrated that aggregation of multiple genetic effects could provide a more comprehensive assessment for AMD patients. It is a good effort indeed. Congratulations to the authors.
Comments for author File: 
Comments.docx
Author Response
Thank you for your review and comments
Reviewer 2 Report
Wasowska et al. investigated the association between polygenic risk score and age-related macular degeneration with PED. There are several concerns to be addressed.
1. PED was classified into serous, hemorrhagic, fibrovascular, and drusenoid PED. What type of PED was included in this study? As described in the Result, were all types included?
2. The definition of PED was not clearly described including size, height, etc.
3. Please describe the controls in detail. Do the controls have any drusen/ pigmentary changes?
4. Authors should cite a recent article regarding drusenoid PED and genetics. PMID: 33920794
5. Are there any differences in PRS among different types in PED?
6. In the Discussion, the authors discussed each gene in detail. It is not enough, please discuss the association between PRS and phenotype, treatment, and prognosis in patients with ocular diseases. These articles would be helpful for the discussion. PMID: 32962278, PMID: 33316263, PMID: 36456827, PMID: 37044160
7 If several PED types were included, the authors mentioned it as a limitation of the study.
Author Response
Please see the attachment.
Author Response File: Author Response.docx
