-->PONE-D-25-63368-->-->Improving performance of polygenic risk scores for hypertension across two ancestry groups.-->-->PLOS One

Dear Dr. Irvin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Hoh Boon-Peng, PhD

Academic Editor

PLOS One

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Additional Editor Comments:

The reviewers have raised several comments, primarily on the LD-fred and the sample stratification.

Authors are invited to response the reviewers point carefully and resubmit the manuscript.

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

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-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

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-->4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The manuscript evaluates the impact of incorporating functional annotations and alternative LD reference panels on PRS performance for hypertension across EA and AA populations. Using two independent cohorts, the authors show that both functional priors and an expanded, multi-ancestry LD reference panel improve PRS performance, with larger gains observed in EA. Overall, the study addresses an important methodological question in PRS development and is suitable for publication. While some issues should be addressed with minor revisions.

1. The larger number of variants included in LDpred-funct scores compared to PRS-CS may explain some of the performance differences. Please clarify whether performance gains reflect functional annotation, variant density, or both. Consider including sensitivity analysis using matched SNP sets or acknowledge this limitation.

2. The methods clearly describe optimization of the PRS-CS phi parameter via grid search in the REGARDS cohort, with the best-performing phi for validation in HyperGEN. Please also clarify in the Results that phi was tuned exclusively in REGARDS and not re-optimized in HyperGEN and confirm whether phi optimization was performed separately by ancestry group.

3. Other minor issues: inconsistent name of LD-Pred-funct vs LDPred-funct. Inconsistent R² formatting. Typo in CI in the Abstract.

Reviewer #2: The authors have done good work benchmarking PRS performance across different models and ancestry groups. However, several issues need clarification or further consideration.

1. Authors should carefully check the numbers in the manuscript. For example,

a) The abstract reports “1,533 EA (58% with HTN)”, whereas the introduction reports “1,598 EA” (page 5, line 107).

b) It was mentioned “variants from a 1000G phase 3 reference panel (including 1,217,312 variants)” in the methods (page 16, line 377), but “3.5M variants” in Table 2.

2. It would be helpful to test LDpred-funct using different LD reference panels (e.g., TagIt vs. HM3) to allow a more direct comparison with PRS-CS and to better identify the effect of the LD panel.

3. Due to the high variation of African ancestry among the AA individuals, it would be meaningful to stratify the AA group according to their African ancestry and further evaluate the performance of PRS within subgroups.

4. How about incorporating the local ancestry as a covariate while analyzing the AA group ? At least, the potential role of local ancestry should be discussed in the manuscript.

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-->6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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-->PONE-D-25-63368R1-->-->Improving performance of polygenic risk scores for hypertension across two ancestry groups.-->-->PLOS One

Dear Dr. Irvin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

The manuscript is generally accepted by the reviewers, except for a few minor comments which I invite the authors to address the comments accordingly.-->--> -->-->==============================

Please submit your revised manuscript by Jul 02 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Hoh Boon-Peng, PhD

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

The manuscript is generally accepted by the reviewers, except for a few minor comments which I invite the authors to address the comments accordingly.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The authors have addressed the points raised in my first review, added sensitivity analysis and corrected typos. I have no further concerns. I recommend acceptance without further revision.

Reviewer #2: The authors have addressed R1 comments well. However, several issues remain and should be clarified:

1. The abstract reports “OR = 1.40; 95% CI 10.8–1.82” (line 21), which was flagged by Reviewer 1. I believe that the authors should carefully verify all numerical values throughout the manuscript.

2. The naming of “LDpred-funct” remains inconsistent. In fact, additional inconsistencies have been introduced in the revised version.

3. The LD panel for LDpred-funct is now changed to “HM3,” whereas the Methods section (lines 394–395) states that LDpred-funct uses a 1000 Genomes Phase 3 reference panel.

4. The restricted SNP-set sensitivity analysis for LDpred-funct (Supplementary Table 3) deserves further discussion. In EAs, the overlapping-SNP LDpred-funct score (OR = 1.74) still outperforms PRS-CS-HM3 (OR = 1.40), but is substantially attenuated compared to the full LDpred-funct score (OR = 2.14). This pattern suggests that while functional annotations contribute meaningfully, SNP density also plays an important role.

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review?  For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

Improving performance of polygenic risk scores for hypertension across two ancestry groups.

PONE-D-25-63368R2

Dear Dr. Irvin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Hoh Boon-Peng, PhD

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: